Articles tagged as "Comorbidity"

Injecting drug use increases risk of TB disease in Indonesians living with HIV

Active and latent tuberculosis among HIV-positive injecting drug users in Indonesia.

Meijerink H, Wisaksana R, Lestari M, Meilana I, Chaidir L, van der Ven AJ, Alisjahbana B, van Crevel R. J Int AIDS Soc. 2015 Feb 16;18(1):19317. doi: 10.7448/IAS.18.1.19317. eCollection 2015.

Introduction: Injecting drug use (IDU) is associated with tuberculosis but few data are available from low-income settings. We examined IDU in relation to active and latent tuberculosis (LTBI) among HIV-positive individuals in Indonesia, which has a high burden of tuberculosis and a rapidly growing HIV epidemic strongly driven by IDU.

Methods: Active tuberculosis was measured prospectively among 1900 consecutive antiretroviral treatment (ART)-naive adult patients entering care in a clinic in West Java. Prevalence of LTBI was determined cross-sectionally in a subset of 518 ART-experienced patients using an interferon-gamma release assay.

Results: Patients with a history of IDU (53.1%) more often reported a history of tuberculosis treatment (34.8% vs. 21.9%, p < 0.001), more often received tuberculosis treatment during follow-up (adjusted HR = 1.71; 95% CI: 1.25-2.35) and more often had bacteriologically confirmed tuberculosis (OR = 1.67; 95% CI: 0.94-2.96). LTBI was equally prevalent among people with and without a history of IDU (29.1 vs. 30.4%, NS). The risk estimates did not change after adjustment for CD4 cell count or ART.

Conclusions: HIV-positive individuals with a history of IDU in Indonesia have more active tuberculosis, with similar rates of LTBI. Within the HIV clinic, LTBI screening and isoniazid preventive therapy may be prioritized to patients with a history of IDU.

Abstract  Full-text [free] access

Editor’s notes: In Europe and northern America, HIV-positive people who inject drugs are at greater risk of TB infection and disease compared with other HIV-positive individuals. In many Asian countries, there is a growing problem of injecting drug use which has contributed to the HIV epidemic. This study explored the association between injecting drug use and TB among people living with HIV in Indonesia. The main analysis included 1900 HIV-positive, ART-naive individuals without TB disease and followed them from enrolment in HIV care to starting TB treatment. Just over half of the study population gave a history of injecting drug use. There was no differentiation between current and historical drug use.

A history of injecting drug use was associated with a 71% increased risk of TB disease during the first year after enrolment in HIV care. This association was maintained after adjusting for age, CD4 cell count and the use of antiretroviral therapy. The association was similar when the analysis was restricted to microbiologically-proven TB disease. The divergence in risk seemed to be early after enrolment, the first six months after entering HIV care. And the majority of TB diagnoses occurred before initiation of ART. This suggests the need for intensified TB diagnostic strategies on enrolment in HIV care. Despite enrolment over almost six years and follow-up for up to six years, the median follow-up was less than a year in the group without a history of injecting drug use. This compares to just under two years for people who inject drugs. This suggests substantial loss to follow-up and may have contributed to the higher observed risk of TB among people who inject drugs. 

This article also reports the prevalence of a positive QuantiFERON Gold In-Tube assay in a separate group of HIV-positive individuals with a median time on ART of over two years. There was no difference in the proportion with a positive QuantiFERON test among individuals with and without a history of injecting drug use. This was a very different study population, however, with a median CD4 cell count >350 cells/µl. Almost half reported previous TB treatment, which makes the QuantiFERON results more difficult to interpret.

These data underline the importance of screening for active TB among people entering HIV care, and of isoniazid preventive therapy for individuals with latent infection.

Avoid TB deaths
Asia
Indonesia
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Lower, long-term risk of TB disease with early versus deferred antiretroviral therapy

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

Collins SE, Jean Juste MA, Koenig SP, Secours R, Ocheretina O, Bernard D, Riviere C, Calnan M, Dunning A, Hurtado Rua SM, Johnson WD, Pape JW, Fitzgerald DW, Severe P. Int J Tuberc Lung Dis. 2015 Jan;19(1):50-7. doi: 10.5588/ijtld.14.0217.

Setting: Port-au-Prince, Haiti.

Objective: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals.

Design: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm3 vs. deferring ART until the CD4 count was <200 cells/mm3. The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up.

Results: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm3, 95% confidence interval [CI] 477-515 vs. 373 cells/mm3, 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis.

Conclusion: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm3 can result in long-term immune dysfunction and persistent increased risk for TB.

Abstract access 

Editor’s notes: There is a solid evidence base to support the initiation of antiretroviral therapy (ART) for adults living with HIV with CD4+ cell count ≤350 cells/µL. One randomised controlled trial in Haiti (CIPRA HT-001) demonstrated a 75% reduction in mortality with initiation of ART at CD4+ cell count 200-350 cells/µL compared to deferring until CD4+ cell count was <200 cells/µL. That same trial demonstrated a 50% reduction in incident TB disease with early ART, over three years of follow-up.

This paper presents a subsequent analysis from this trial with extended follow-up to five years. This analysis reports on whether or not the effect of early ART was maintained, and the long-term effect on CD4+ recovery. The beneficial impact of early ART on incident TB disease was indeed maintained over the five years of follow-up. Half of the TB cases in the deferred ART group occurred before the initiation of ART but the differential risk persisted beyond the initiation of ART. 

There was also a clear benefit of early ART on immune recovery. More than 75% of participants in the early ART group achieved a CD4+ cell count >500 cells/µL by five years, compared to fewer than 25% of people in the deferred ART group. The effect of early ART on incident TB was only partially modified after adjustment for time-updated CD4+ cell count, suggesting that early ART has benefit over and above its effect on CD4+ cell count recovery.

Although this is clear evidence to start ART promptly in people with severe immunosupression, these data do not address the question of whether ART at CD4+ cell counts above 350 cells/µL influences the risk of TB disease, and this information is eagerly awaited from ongoing clinical trials. 

Avoid TB deaths
Latin America
Haiti
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TB pre- and post- antiretroviral therapy initiation in India

Incidence and mortality of tuberculosis before and after initiation of antiretroviral therapy: an HIV cohort study in India.

Alvarez-Uria G, Pakam R, Midde M, Naik PK. J Int AIDS Soc. 2014 Dec 9;17:19251. doi: 10.7448/IAS.17.1.19251. eCollection 2014.

Introduction: India has the highest burden of tuberculosis (TB) in the world, but the epidemiology of HIV-associated TB is not well known.

Methods: We describe the incidence and the mortality of TB from HIV diagnosis to antiretroviral therapy (ART) initiation (pre-ART group) and after ART initiation (on-ART group) in an HIV cohort study in Anantapur, India. Multivariable analysis of factors associated with TB was performed using competing risk regression and restricted cubic spline methods.

Results: A total of 4590 patients and 3133 person-years (py) of follow-up were included in the pre-ART group, and 3784 patients and 4756 py were included in the on-ART group. In the pre-ART group, the incidence of TB was high during the first month after HIV diagnosis and dropped nearly four times soon after. In the on-ART group, the incidence of TB increased after ART initiation reaching a peak in the third month. The probability of having TB within 30 months was 22.3% (95% confidence interval [CI], 21.1-23.6) in the pre-ART group and 17.8% (95% CI, 16.3-19.3) in the on-ART group. In a multivariable analysis, women had a lower risk of TB in both groups. Poor socio-economic conditions were associated with an increased risk of TB in the pre-ART group, but not in the group on-ART. While the association between low CD4 counts and TB was strong in the pre-ART group, this association was weaker in the on-ART group, and the highest risk of TB was seen in those patients with CD4 counts around 110 cells/mm3. The cumulative incidence of mortality at 12 months in patients with TB was 29.6% (95% CI, 26.9-32.6) in pre-ART TB and 34.9% (95% CI, 31-39.1) in on-ART TB. Half deaths before ART initiation and two thirds of deaths after ART initiation occurred in patients with TB.

Conclusions: The high incidence and mortality of TB seen in this study underscore the urgent need to improve the prevention and diagnosis of HIV-associated TB in India. We found substantial differences between TB before and after ART initiation.

Abstract  Full-text [free] access

Editor’s notes: Although India has a huge burden of TB, there are relatively few published data regarding the epidemiology of HIV-associated TB, which this retrospective analysis begins to address. This study describes the incidence of TB and mortality among people with TB. The study looked at a cohort of people living with HIV, attending a rural hospital funded by a non-governmental organisation where medical care, including antiretroviral therapy and TB treatment, were provided free of charge. The authors report extremely high incidence of TB shortly after both HIV diagnosis and antiretroviral therapy initiation. They also report high mortality among individuals with TB, all of which are far greater than described in antiretroviral therapy programmes in South Africa. As the authors note, this likely reflects multiple issues. These include the fact that people often first present for HIV care due to symptoms of TB, unsatisfactory screening for TB, and inadequate investigation of individuals with TB symptoms, which relies on sputum microscopy and radiology. Furthermore, isoniazid preventive therapy is not yet implemented in India and the authors report that buildings designated as antiretroviral therapy centres are often inadequate in terms of infection control. This study highlights the urgency of comprehensive implementation of WHO’s three I’s (intensified case finding, isoniazid preventive therapy, infection control) for tuberculosis strategy in this setting and access to better, affordable and rapid diagnostic tests for TB.

Avoid TB deaths
Asia
India
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Successful malaria prevention for HIV-exposed children

Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial.

Kamya MR, Kapisi J, Bigira V, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Kakuru A, Aweeka FT, Huang L, Jagannathan P, Achan J, Havlir DV, Rosenthal PJ, Dorsey G. AIDS. 2014 Nov 28;28(18):2701-9. doi: 10.1097/QAD.0000000000000497.

Objective: Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.

Design: An open-label, randomized controlled trial.

Setting: Tororo, Uganda, a rural area with intense, year-round, malaria transmission.

Participants: Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).

Intervention: No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.

Main outcome measures: The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.

Results: During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.

Conclusion: Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

Abstract access 

Editor’s notes: WHO recommends placing HIV-exposed but HIV-negative children on trimethoprim-sulfamethoxazole prophylaxis starting at six weeks of age, and discontinuing this prophylaxis after the period of HIV exposure. That is after breastfeeding cessation and HIV infection has been excluded.

This article reports on a four-arm randomized controlled trial examining the effect of chemoprevention beyond the period of HIV exposure. The efficacy and safety of daily trimethoprim-sulfamethoxazole, monthly sulfadoxine-pyrimethamine, and monthly dihydroartemisinin-piperaquine was compared with the current standard of care which is no chemoprevention beyond the period of HIV exposure. Children received the allocated treatment until two years of age. They were followed up for an additional year after the programme to examine whether chemoprevention would delay the acquisition of antimalarial immunity, which would lead to a rebound in the incidence of malaria after the activity, was stopped.

The trial found that continuing daily trimethoprim-sulfamethoxazole or starting monthly dihydroartemisinin-piperaquine had significant protective efficacy against malaria in comparison to the current standard of care which is the discontinuation of trimethoprim-sulfamethoxazole prophylaxis. Monthly dihydroartemisinin-piperaquine was found to be the most protective chemoprevention.

The trial found no evidence of significant protection against diarrhoeal illnesses or respiratory tract infections, and no evidence of a negative impact of chemoprevention on the development of antimalarial immunity. The authors suggest that integration of chemoprevention strategies for HIV-exposed but HIV-negative children in the era of Option B+ (initiating lifelong antiretroviral therapy among pregnant women living with HIV) needs to be further evaluated.

Interestingly the authors found a high incidence of malaria in the children who were receiving standard care, despite the use of insecticide-treated nets. They also found a discrepancy between the caregivers’ reported adherence to dihydroartemisinin-piperaquine and its blood concentrations, suggesting non-adherence to the monthly dosing schedule. 

Avoid TB deaths
Comorbidity
Africa
Uganda
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HIV and disability – a stronger link than perhaps we thought?

When I was no longer able to see and walk, that is when I was affected most: experiences of disability in people living with HIV in South Africa.

Hanass-Hancock J, Myezwa H, Nixon SA, Gibbs A. Disabil Rehabil. 2014 Dec 19:1-11. [Epub ahead of print]

Abstract Purpose: HIV-related disability is an emerging issue in countries where HIV is endemic. This study aimed to understand experiences of disability in patients living with HIV in South Africa using the International Classification of Functioning, Disability and Health (ICF) as a guiding framework.

Methods: In-depth interviews were conducted with 19 HIV-positive people receiving ART through a public hospital in KwaZulu-Natal. Data were analyzed using collaborative qualitative content analysis.

Results: Participants described a variety of impairments related to mental, sensory, neuromusculoskeletal, skin, cardiovascular, digestive or reproductive systems. A tenuous relationship was evident between HIV and mental health impairments and the experience of other disabilities. Impairments affected participants' activity levels, especially mobility, domestic life, self-care and ability to work. Activity limitations affecting livelihood were often of more concern to participants than the impairments. Furthermore, women and men appeared to experience disability related to activities relevant to gendered norms in their cultural context.

Conclusions: More understanding of the intersections among HIV, disability, gender and livelihood is needed. To respond to the increased need to manage disability within HIV care in Africa, HIV programs should include rehabilitative approaches, address concerns related to livelihoods in households with disability and consider gender differences in the experience of disability.

Implications for Rehabilitation: HIV, its opportunistic infections and the treatments associated to them are related to health conditions and impairments that have the potential to develop into disability. Rehabilitation professionals in HIV endemic countries have therefore a larger and changing number of people living with HIV and need to consider the impact of the disease on the rehabilitation process. Mental health issues and disability might be interrelated and affect antiretroviral treatment (ART) adherence. Hence, rehabilitation has to use a holistic approach and integrate different therapy approaches (e.g. physiotherapy and mental health). The experience of living with HIV and developing disability has unreflected gender dynamics that need to be considered in rehabilitative care. Hence, the rehabilitation process has to consider the cultural realities and gendered experience of the condition. The study highlights the interrelationship between disability levels, the influence of environmental and social factors, and the changing experience related to gender. Hence, rehabilitation professionals in resource-poor settings have to go beyond the clinical response and therapy approaches in order to improve the activity and participation of people with disabilities and those living with HIV in their homes and communities. Community or home-based care might be avenues to further explore.

Abstract access 

Editor’s notes: While the existence of disability among people living with HIV and on antiretroviral therapy (ART) has been reported, few studies have investigated the individual’s experience of disability. This important study from South Africa aims to fill that gap. The authors used WHO International Classification of Functioning, Disability and Health (ICF) to guide their interviews and the analysis. They systematically sampled participants from an antiretroviral treatment clinic at a public hospital in KwaZulu-Natal. Importantly they did not purposely choose people with a visible disability because they wished to capture the perspectives of people who appeared to being doing well on ART as well as people who may have a visible impairment. No screening for disability was done prior to recruitment in the study. Ten of the 19 participants had no visible disability, but 17 out of 19 reported challenges at the impairment level of disability. These challenges were often related to mental function, sensory function and pain, headaches, painful feet and vision problems (which in some cases seemed to be linked to TB treatment). These different impairments affected mobility, social interactions, ability to make a living and self-esteem. Not all of these impairments were visible nor necessarily reported to clinic staff who perceived many of these people to be ‘doing well’ on ART.  The authors illustrate in this small but important study a great diversity of experience of disability across a small number of people in one clinic in South Africa. They highlight the importance of understanding the social and environmental factors which influence individual experience. Most importantly they stress the need to pay attention to impairment and the rehabilitation support that may be needed, even for people who appear to be doing well on medication.

Africa
South Africa
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Brazil - long-term protection from TB with six months of isoniazid preventive therapy

Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium-burden tuberculosis setting: the TB/HIV in Rio (THRio) study.

Golub JE, Cohn S, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, Durovni B, Chaisson RE. Clin Infect Dis. 2014 Nov 2. pii: ciu849. [Epub ahead of print]

Background: The duration of protection against tuberculosis provided by isoniazid preventive therapy is not known for human immunodeficiency virus (HIV)-infected individuals living in settings of medium tuberculosis incidence.

Methods: We conducted an individual-level analysis of participants in a cluster-randomized, phased-implementation trial of isoniazid preventive therapy. HIV-infected patients who had positive tuberculin skin tests (TSTs) were followed until tuberculosis diagnosis, death, or administrative censoring. Nelson-Aalen cumulative hazard plots were generated and hazards were compared using the log-rank test. Cox proportional hazards models were fitted to investigate factors associated with tuberculosis diagnosis.

Results: Between 2003 and 2009, 1954 patients with a positive TST were studied. Among these, 1601 (82%) initiated isoniazid. Overall tuberculosis incidence was 1.39 per 100 person-years (PY); 0.53 per 100 PY in those who initiated isoniazid and 6.52 per 100 PY for those who did not (adjusted hazard ratio [aHR], 0.17; 95% confidence interval [CI], .11-.25). Receiving antiretroviral therapy at time of a positive TST was associated with a reduced risk of tuberculosis (aHR, 0.69; 95% CI, .48-1.00). Nelson-Aalen plots of tuberculosis incidence showed a constant risk, with no acceleration in 7 years of follow-up for those initiating isoniazid preventive therapy.

Conclusions: Isoniazid preventive therapy significantly reduced tuberculosis risk among HIV-infected patients with a positive TST. In a medium-prevalence setting, 6 months of isoniazid in HIV-infected patients with positive TST reduces tuberculosis risk over 7 years of follow-up, in contrast to results of studies in higher-burden settings in Africa.

Abstract access 

Editor’s notes: Isoniazid preventive therapy (IPT) is a key component of WHO strategy to reduce the burden of tuberculosis among people living with HIV. In early randomised trials among people living with HIV, the duration of IPT was usually six months. This was consistently found to be effective in reducing TB incidence among people with a positive tuberculin skin test (TST). However, more recent studies from southern Africa have found that this protective effect wanes rapidly after the IPT course is completed. These studies have led to policy recommendations for continuous IPT for people living with HIV who are TST positive. In addition, mathematical modelling of trial data has suggested that IPT may not “cure” latent TB infection in people living with HIV.

There are few data from settings with lower TB transmission documenting the durability of short-course IPT among people living with HIV. This paper reports long-term follow-up among people living with HIV who received IPT in the THRio study in Brazil, a medium TB burden setting. The data provides reassurance that a six-month course of IPT gives durable protection against TB among people living with HIV. Nonetheless, there is a need for implementation of shorter, effective TB preventive therapy regimens, which are less arduous for people and simpler for health services to deliver.

Avoid TB deaths
Comorbidity
Latin America
Brazil
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Antiretroviral therapy alone not enough to reduce TB incidence where HIV- and TB- prevalence is high

Incidence of HIV-associated tuberculosis among individuals taking combination antiretroviral therapy: a systematic review and meta-analysis.

Kufa T, Mabuto T, Muchiri E, Charalambous S, Rosillon D, Churchyard G, Harris RC. PLoS One. 2014 Nov 13;9(11):e111209. doi: 10.1371/journal.pone.0111209. eCollection 2014.

Background: Knowledge of tuberculosis incidence and associated factors is required for the development and evaluation of strategies to reduce the burden of HIV-associated tuberculosis.

Methods: Systematic literature review and meta-analysis of tuberculosis incidence rates among HIV-infected individuals taking combination antiretroviral therapy.

Results: From PubMed, EMBASE and Global Index Medicus databases, 42 papers describing 43 cohorts (32 from high/intermediate and 11 from low tuberculosis burden settings) were included in the qualitative review and 33 in the quantitative review. Cohorts from high/intermediate burden settings were smaller in size, had lower median CD4 cell counts at study entry and fewer person-years of follow up. Tuberculosis incidence rates were higher in studies from sub-Saharan Africa and from World Bank low/middle income countries. Tuberculosis incidence rates decreased with increasing CD4 count at study entry and duration on combination antiretroviral therapy. Summary estimates of tuberculosis incidence among individuals on combination antiretroviral therapy were higher for cohorts from high/intermediate burden settings compared to those from the low tuberculosis burden settings (4.17 per 100 person-years [95% Confidence Interval (CI) 3.39-5.14 per 100 person-years] vs. 0.4 per 100 person-years [95% CI 0.23-0.69 per 100 person-years]) with significant heterogeneity observed between the studies.

Conclusions: Tuberculosis incidence rates were high among individuals on combination antiretroviral therapy in high/intermediate burden settings. Interventions to prevent tuberculosis in this population should address geographical, socioeconomic and individual factors such as low CD4 counts and prior history of tuberculosis.

Abstract Full-text [free] access

Editor’s notes: This systematic review and meta-analysis looks at tuberculosis (TB) incidence rates among adults living with HIV on antiretroviral treatment (ART). The review reinforces and quantifies what we already know about the disparities between low-burden and high-burden settings. TB incidence rates in high and intermediate burden settings are ten times higher than those in low burden settings.

The authors draw attention to the need for implementation of programmes that address the social determinants of TB. Low socio-economic conditions are associated with higher TB incidence rates in individuals on ART. Interestingly, the meta-analysis found that TB incidence rates were higher among individuals on ART who had a previous history of TB, than individuals who did not have a history of previous TB. The epidemiological association between previous TB treatment and active TB was one of the foundations for the emphasis on case retention and cure rates with the Directly Observed Treatment, Short-Course (DOTS) strategy. Yet prevalence surveys conducted in Zimbabwe, South Africa and Zambia in the pre-ART and early ART era did not find an association between a history of previous TB and prevalent active undiagnosed TB in individuals living with HIV. The finding from this meta-analysis suggests that individuals on ART are now surviving long enough to develop recurrent TB disease.

The overall message of the study is that ART alone is not sufficient to reduce TB incidence in high HIV prevalence settings. Additional strategies are required to prevent TB focussing on individuals with low CD4 counts, a history of previous TB disease and people who have recently initiated ART.

Avoid TB deaths
Africa, Asia, Europe, Northern America
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Reduction in the incidence of invasive pneumococcal disease following vaccination

Effects of vaccination on invasive pneumococcal disease in South Africa.

von Gottberg A, de Gouveia L, Tempia S, Quan V, Meiring S, von Mollendorf C, Madhi SA, Zell ER, Verani JR, O'Brien KL, Whitney CG, Klugman KP, Cohen C; GERMS-SA Investigators. N Engl J Med. 2014 Nov 13;371(20):1889-99. doi: 10.1056/NEJMoa1401914. Epub 2014 Nov 11.

Background: In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease.

Methods: We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups.

Results: Surveillance identified 35 192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100 000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100 000 person-years in disease caused by PCV7 serotypes (-89%; 95% confidence interval [CI], -92 to -86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, -89 to -79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, -63 to -50), from 3.7 to 1.6 cases per 100 000 person-years.

Conclusions: Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination.

Abstract Full-text [free] access

Editor’s notes: There has been a marked reduction in invasive pneumococcal disease in high-income settings following the roll-out of pneumococcal conjugate vaccine. The reduction in incidence of pneumococcal disease has been observed not just among vaccinated infants but also among older children and adults, indicating herd immunity. This study is the first to report on the population impact of pneumococcal vaccination given at six weeks, 14 weeks and nine months of age in an African setting with a high prevalence of HIV and high antiretroviral therapy coverage. Following the introduction of infant pneumococcal vaccination in 2009, the incidence of laboratory reported invasive pneumococcal disease (defined as hospitalised person with positive cultures from sterile sites) declined by 89% for pneumococcal conjugate vaccine -7 (PCV-7) serotypes. A reduction in the incidence of non-vaccine serotypes of 20% indicates that some, but not all of this reduction may be due to improvements in HIV care and increasing antiretroviral therapy coverage. As observed in high-income settings the benefits were seen not just in infants but also in older children and adults. Reassuringly, a reduced incidence of pneumococcal disease was found in individuals living with HIV and in people who did not have the disease. While there was some indication that serotype replacement may become a future problem (small increase in invasive diseases caused by non-vaccine serotypes in HIV negative infants) longer follow-up data is required to fully explore this issue.

Avoid TB deaths
Africa
South Africa
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High frequency of drug-resistant TB in HIV clinics in India

Alarming levels of drug-resistant tuberculosis in HIV-infected patients in metropolitan Mumbai, India.

Isaakidis P, Das M, Kumar AM, Peskett C, Khetarpal M, Bamne A, Adsul B, Manglani M, Sachdeva KS, Parmar M, Kanchar A, Rewari BB, Deshpande A, Rodrigues C, Shetty A, Rebello L, Saranchuk P. PLoS One. 2014 Oct 21;9(10):e110461. doi: 10.1371/journal.pone.0110461. eCollection 2014.

Background: Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India.

Methods: A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases.

Results: Between March 2013 and January 2014, ART-center attendees were screened during 14 135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%-40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models.

Conclusion: The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with 'presumptive TB' rather than 'presumptive DR-TB' and tailor the treatment regimen based on the resistance patterns.

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Editor’s notes: Drug-resistant tuberculosis (TB) is a major threat to public health. It is associated with substantial morbidity and mortality, particularly among people with advanced HIV disease. Standard drug regimens for multi- and extensively drug-resistant TB are unsatisfactory, requiring long courses of treatment with drugs which often have unpleasant and sometimes serious side effects. For TB programmes, treating drug-resistant TB requires substantial resources, and presents a risk to health care workers unless infection control measures are rigorously applied. 

In this study at five HIV treatment centres in Mumbai, India, adults and children attending for HIV care were systematically screened for TB by a research nurse. Individuals reporting one or more TB symptom (any of cough, weight loss, night sweats or fever, referred to in the article as people with “presumptive TB”) had sputum sent for microscopy, culture and drug susceptibility testing. Among individuals who had Mycobacterium tuberculosis on culture, some 34% had resistance to any drug. Among individuals who had never previously been treated for TB, 11% had resistance to at least rifampicin and isoniazid (multidrug-resistant tuberculosis), and several had more extensive resistance patterns. Among 15 children with culture-positive TB, seven had resistance to at least one drug, and six had at least multidrug-resistant TB. This is particularly concerning because it implies transmission of drug-resistant tuberculosis either in the community or in health care facilities or both.

As the authors illustrate, the absolute number of TB cases was relatively small, and the findings may not be generalisable to other settings in India. Nonetheless, the findings indicate transmission of drug-resistant TB among people living with HIV attending these clinics. This study underlines the need for early detection and prompt initiation of effective treatment for people with TB, including individuals with drug-resistant TB, and for infection control measures to protect individuals and staff within clinics.

Avoid TB deaths
Comorbidity
Asia
India
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Cervical cancer screening programmes in resource-limited settings

Clinical performance of digital cervicography and cytology for cervical cancer screening in HIV-infected women in Lusaka, Zambia.

Bateman AC, Parham GP, Sahasrabuddhe VV, Mwanahamuntu MH, Kapambwe S, Katundu K, Nkole T, Mulundika J, Pfaendler KS, Hicks ML, Shibemba A, Vermund SH, Stringer JS, Chibwesha. J Acquir Immune Defic Syndr. 2014 Oct 1;67(2):212-5. doi: 10.1097/QAI.0000000000000270.

Although there is a growing literature on the clinical performance of visual inspection with acetic acid in HIV-infected women, to the best of our knowledge, none have studied visual inspection with acetic acid enhanced by digital cervicography. We estimated clinical performance of cervicography and cytology to detect cervical intraepithelial neoplasia grade 2 or worse. Sensitivity and specificity of cervicography were 84% (95% confidence interval [CI]: 72 to 91) and 58% (95% CI: 52 to 64). At the high-grade squamous intraepithelial lesion or worse cutoff for cytology, sensitivity and specificity were 61% (95% CI: 48 to 72) and 58% (95% CI: 52 to 64). In our study, cervicography seems to be as good as cytology in HIV-infected women.

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Editor’s notes: Cervical cancer is the most common female malignancy in sub-Saharan Africa and the leading cause of cancer-related mortality. Women living with HIV have a higher incidence and prevalence of infection with human papilloma virus (HPV), and are less able to clear the virus. Persistence of high-risk types of HPV infection is a prerequisite for development of cervical cancer. In high-income countries, screening programmes which incorporate regular cervical cytology (one to five yearly) to detect pre-cancerous lesions, have reduced mortality; however cytology is labour intensive and technically challenging. As a result cervical screening is not widely available in resource-limited settings. Alternative screening strategies, including visual inspection with acetic acid (VIA) with onward referral for colposcopy if abnormal lesions are visualised, are practiced in some settings, although coverage is low.

This study reports on the sensitivity and specificity of VIA enhanced by digital photography. The addition of digital photography allows magnification of surface morphology, and facilitates telemedicine support and quality assurance of screening programmes.  All individuals had cytology, VIA, photographs and biopsies taken at the same visit. Cervical biopsies were taken from the abnormal area and from a normal area of the transformation zone with the gold standard defined as cervical intraepithelial neoplasia grade 2or 3 or adenocarcinoma in situ (CIN2+) lesion on histopathology of either site. VIA with digital photography had a higher sensitivity than cytology (84% and 61% respectively) but specificity was low with both techniques (58% each). Results are broadly comparable to those reported from other studies evaluating VIA in women living with HIV. This approach is certainly more feasible to implement in resource-limited settings and if programme coverage is high, may impact on mortality. However, given the low specificity, over-treatment is likely. As the authors illustrate there is definitely a need to develop other screening strategies based on point-of-care biomarkers if we are to see a significant impact on mortality due to cervical cancer in resource-limited settings.

Avoid TB deaths
Africa
Zambia
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