Articles tagged as "Health systems and services"

Fewer deaths with empirical TB treatment among seriously ill people

Empiric TB treatment of severely ill patients with HIV and presumed pulmonary TB improves survival.

Katagira W, Walter ND, den Boon S, Kalema N, Ayakaka I, Vittinghoff E, Worodria W, Cattamanchi A, Huang L, Davis JL. J Acquir Immune Defic Syndr. 2016 Feb 24. [Epub ahead of print]

Rationale: In 2007, WHO issued emergency recommendations on empiric treatment of sputum acid-fast bacillus (AFB) smear-negative patients with possible tuberculosis (TB) in HIV-prevalent areas, and called for operational research to evaluate their effectiveness. We sought to determine if early, empiric TB treatment of possible TB patients with abnormal chest radiography or severe illness as suggested by the 2007 WHO guidelines is associated with improved survival.

Methods: We prospectively enrolled consecutive HIV-seropositive inpatients at Mulago Hospital in Kampala, Uganda, from 2007 to 2011 with cough 2 weeks. We retrospectively examined the effect of empiric TB treatment before discharge on eight-week survival among those with and without a WHO-defined 'danger sign,' including fever >39 degrees C, tachycardia >120 beats-per-minute, or tachypnea >30 breaths-per-minute. We modeled the interaction between empiric TB treatment and danger signs and their combined effect on eight-week survival and adjusted for relevant covariates.

Results: Among 631 sputum smear-negative patients, 322(51%) had danger signs. Cumulative eight-week survival of patients with danger signs was significantly higher with empiric TB treatment (80%) than without (64%, p<0.001). After adjusting for duration of cough and concurrent hypoxemia, patients with danger signs who received empiric TB treatment had a 44% reduction in eight-week mortality(Risk Ratio 0.54, 95%CI 0.32-0.91, p=0.020).

Conclusions: Empiric TB treatment of HIV-seropositive, smear-negative, presumed pulmonary TB patients with one or more danger signs is associated with improved eight-week survival. Enhanced implementation of the 2007 WHO empiric-treatment recommendations should be encouraged whenever and wherever rapid and highly sensitive diagnostic tests for TB are unavailable.

Abstract access

Editor’s notes: TB remains the most important cause of death among people living with HIV worldwide. Empirical TB treatment, meaning treatment without bacteriological confirmation, is common practice among people with symptoms suggesting TB, where diagnostic tests are unsatisfactory and the risk of death is high if TB were left untreated.

WHO recommends empirical TB treatment for people living with HIV who are seriously ill, for example as indicated by one or more “danger signs” (respiratory rate over 30 per minute, temperature over 39ºC, pulse over 120, unable to walk unaided).  However the evidence to guide the use of empirical TB treatment is very limited. This study adds to that evidence base. HIV-positive adult in-patients with a cough of at least two weeks duration were recruited as part of a study of pneumonia, in a referral hospital in Uganda, and underwent a standard set of investigations. This sub-analysis included people who were sputum smear negative, and investigated the association of empirical TB treatment with survival at eight weeks. Among individuals who had one or more danger signs, people who were treated for TB were more likely to be alive at eight weeks (80% versus 64%). Among people without danger signs, mortality was not associated with empirical TB treatment (survival at eight weeks, 76% among people treated empirically versus 74% among people not treated).

It is important to keep in mind that this was an observational cohort, not a randomised trial, and the implementation of empirical TB treatment according to WHO guidelines was far from complete. Among HIV-positive adults eligible for the study (cough for at least two weeks and sputum smear negative), over half had one or more danger signs, but only 23% of them received TB treatment. Some 20% of the people included in the study were already taking antiretroviral therapy (ART). It is implied that few started ART during admission, and this may also have contributed to high mortality.

This study is particularly relevant in the context of the results of two recent trials of empirical TB treatment. One, the REMEMBER trial will be discussed in next month’s digest. Briefly this study found no mortality benefit of empirical TB treatment over isoniazid preventive therapy among HIV-positive people with CD4 counts below 50 among whom locally-available diagnostic tests had not detected TB. The other trial, TB Fast Track, was presented at CROI in February. This trial found no difference in mortality among adult out-patients, with CD4 counts of 150 or fewer. The patients were managed according to a nurse-led algorithm using point of-care tests to stratify TB risk. Immediate empirical TB treatment for people at highest risk was compared to standard management. The results of all these studies should lead to better definition of criteria for the use of empirical TB treatment. Ultimately, however, better tests for TB that can be used in primary care settings are urgently needed. 

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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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Exploring community perceptions of community health workers roles in chronic disease management in western Kenya.

Community perceptions of community health workers (CHWs) and their roles in management for HIV, tuberculosis and hypertension in western Kenya.

Rachlis B, Naanyu V, Wachira J, Genberg B, Koech B, Kamene R, Akinyi J, Braitstein P. PLoS One. 2016 Feb 22;11(2):e0149412. doi: 10.1371/journal.pone.0149412. eCollection 2016.

Given shortages of health care providers and a rise in the number of people living with both communicable and non-communicable diseases, Community Health Workers (CHWs) are increasingly incorporated into health care programs. We sought to explore community perceptions of CHWs including perceptions of their roles in chronic disease management as part of the Academic Model Providing Access to Healthcare Program (AMPATH) in western Kenya. In depth interviews and focus group discussions were conducted between July 2012 and August 2013. Study participants were purposively sampled from three AMPATH sites: Chulaimbo, Teso and Turbo, and included patients within the AMPATH program receiving HIV, tuberculosis (TB), and hypertension (HTN) care, as well as caregivers of children with HIV, community leaders, and health care workers. Participants were asked to describe their perceptions of AMPATH CHWs, including identifying the various roles they play in engagement in care for chronic diseases including HIV, TB and HTN. Data was coded and various themes were identified. We organized the concepts and themes generated using the Andersen-Newman Framework of Health Services Utilization and considering CHWs as a potential enabling resource. A total of 207 participants including 110 individuals living with HIV (n = 50), TB (n = 39), or HTN (n = 21); 24 caregivers; 10 community leaders; and 34 healthcare providers participated. Participants identified several roles for CHWs including promoting primary care, encouraging testing, providing education and facilitating engagement in care. While various facilitating aspects of CHWs were uncovered, several barriers of CHW care were raised, including issues with training and confidentiality. Suggested resources to help CHWs improve their services were also described. Our findings suggest that CHWs can act as catalysts and role models by empowering members of their communities with increased knowledge and support.

Abstract  Full-text [free] access 

Editor’s notes: As community-health workers are becoming an integrated part of the health care systems in Kenya, more information is required on how they are perceived by the communities they serve. This qualitative study explores perceptions on the role of community-health workers in chronic disease management.

Generally, community health workers are well received by the communities. They are perceived as an enabling resource in generating awareness on specific health issues and promoting positive health seeking behaviours. However, some negative perceptions were raised by several study participants, including their inability to maintain confidentiality and their sometimes limited or inaccurate knowledge on specific health issues, due to limited training.

Suggested resources to strengthen the role of community health workers in engaging communities in chronic disease management include additional training. Also information tools e.g. brochures, posters and charts and participation in larger communities’ awareness events e.g. through community gatherings. These findings are particularly useful for other community-health worker programmes to promote positive health seeking behaviours including successful linkage and retention in care.

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Treating vaginal infections lowers risk of sexually transmitted bacterial infections

Periodic presumptive treatment for vaginal infections may reduce the incidence of bacterial sexually transmitted infections.

Balkus JE, Manhart LE, Lee J, Anzala O, Kimani J, Schwebke J, Shafi J, Rivers C, Kabare E, McClelland RS. J Infect Dis. 2016 Feb 4. pii: jiw043. [Epub ahead of print]

Background: Bacterial vaginosis (BV) may increase women's susceptibility to sexually transmitted infections (STIs). In a randomized trial of periodic presumptive treatment (PPT) to reduce vaginal infections, we observed a significant reduction in BV. We further assessed the intervention effect on incident Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), and Mycoplasma genitalium (MG).

Methods: Non-pregnant, HIV-uninfected women from the US and Kenya received intravaginal metronidazole 750mg plus miconazole 200mg or placebo for 5 consecutive nights each month for 12 months. Genital fluid specimens were collected every other month. Poisson regression models were used to assess the intervention effect on STI acquisition.

Results: Of 234 women enrolled, 221 had specimens available for analysis. Incidence of any bacterial STI (CT, GC, or MG) was lower in the intervention arm compared to placebo (incidence rate ratio [IRR]=0.54, 95% CI 0.32-0.91). When assessed individually, reductions in STIs were similar but not statistically significant (CT:IRR=0.50, 95% CI 0.20-1.23; GC:IRR=0.56, 95% CI 0.19-1.67; MG:IRR=0.66, 95% CI 0.38-1.15).

Conclusions: In addition to reducing BV, this PPT intervention may also reduce women's bacterial STI risk. Because BV is highly prevalent, often persists, and frequently recurs after treatment, interventions that reduce BV over extended periods could play a role in decreasing STI incidence globally.

Abstract access

Editor’s notes: Increasing attention is being paid to the health of vaginal microbiota. Disruption of the vaginal microbiota i.e. dysbiosis, is thought to increase susceptibility to other sexually transmitted infections, including HIV. While considerable observational data support the hypothesis of vaginal dysbiosis being a risk factor for sexually transmitted infection, the hypothesis has not been confirmed through randomized control trials. Women in the programme arm of this randomized control trial were presumptively treated for bacterial vaginosis and vulvovaginal candidiasis on a monthly basis. Relative to the control arm, the women in the programme arm had approximately half the risk of infection by Chlamydia trachomatis, Neisseria gonorrhoea or Mycoplasma genitalium. The findings provide strong evidence for considering healthy vaginal flora as a protective factor from sexually transmitted bacterial infections. Further research must consider whether the protection extends to sexually transmitted viruses and protozoa, and for adolescents and women who are not of African heritage.

Africa, Northern America
Kenya, United States of America
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Spatial analysis methods to improve localised estimates of HIV prevalence

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

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

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

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

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

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

Abstract access  

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

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

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

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

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Tuberculous meningitis: what more can we do?

Intensified antituberculosis therapy in adults with tuberculous meningitis.

Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M, Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ. N Engl J Med. 2016 Jan 14;374(2):124-34. doi: 10.1056/NEJMoa1507062.

Background: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients.

Methods: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization.

Results: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08).

Conclusions: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment.

Abstract  Full-text [free] access 

Editor’s notes: This was a well-designed and rigorously conducted clinical trial in two tertiary referral hospitals in Viet Nam. The underlying hypothesis that intensified TB treatment might improve outcomes was based on reasonable pharmacokinetic and clinical evidence. The findings are therefore disappointing and raise more questions about how to improve outcomes from TB meningitis.

In this trial, 43% of participants were HIV-positive. Two-thirds of participants were ART-naïve and the median CD4+ count was 38 cells/µL. Almost 40% of HIV-positive participants had died by nine months. Most deaths occurred in the first month. For people that were ART-naïve, two-thirds of deaths occurred before the scheduled start of ART (eight weeks). Interestingly, mortality was not affected by being on ART at enrolment, although higher CD4+ count was associated with lower mortality. Overall, the strongest predictors of mortality were rifampicin resistance and the severity of disease at enrolment.

There is a need for continued research to optimise treatment strategies for TB meningitis. Additional analyses from this trial should help to inform this research agenda. These data also clearly highlight the need to develop strategies upstream in the health system and community to ensure earlier diagnosis and treatment of both TB and HIV. 

Comorbidity, HIV Treatment
Viet Nam
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Continuous IPT: benefits in TB prevalent settings

Continuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV: a systematic review and meta-analysis.

Boon SD, Matteelli A, Ford N, Getahun H. AIDS. 2016 Jan 4. [Epub ahead of print]

Objective: This systematic review was carried out to determine the effectiveness of continuous isoniazid (given for at least 36 months) for the treatment of latent tuberculosis infection (LTBI) in people living with HIV (PLHIV).

Methods: Six databases and HIV and tuberculosis (TB) conference abstract books were searched for randomized controlled trials that compared the effectiveness of continuous isoniazid treatment with 6 months of isoniazid application. Outcomes of interest were TB incidence, mortality, adverse events and risk of drug resistance. Data were pooled using fixed-effects meta-analysis.

Results: Three studies were included, from Botswana, South Africa and India. The risk of active TB was 38% lower among patients receiving continuous isoniazid compared with isoniazid regimen for 6 months [relative risk (RR) 0.62, 95% confidence interval (CI): 0.42-0.89; I = 0%], and 49% lower for those with a positive tuberculin skin test (TST) (RR 0.51, 95% CI: 0.30-0.86; I = 7%). Similarly, individuals with positive TST had a 50% lower chance of death (RR 0.50, 95% CI: 0.27-0.91; I = 3%). Two studies found no evidence of an increase in adverse events in the continuous isoniazid group, whereas a third study, that used a different definition for adverse events, found strong evidence of increase. There was no evidence of increased drug resistance when continuous isoniazid was given.

Conclusion: For PLHIV in settings with high TB and HIV prevalence and transmission, continuous isoniazid for at least 36 months is beneficial and probably outweighs the risk of increased adverse events compared with isoniazid regimen for 6 months.

Abstract access 

Editor’s notes: Isoniazid preventive therapy (IPT) reduces TB incidence among HIV-positive people. Evidence has accumulated from settings where TB is prevalent that the protective effect of a standard six-month course of isoniazid wanes after treatment stops. This may be because of reinfection with rapid progression to TB disease. However, in high transmission settings, where the bacillary burden of latent infection could be higher, six months of isoniazid may be insufficient to “cure” latent tuberculosis infection, and reactivation of residual latent infection may also contribute to TB disease after IPT is discontinued. 

This meta-analysis puts together data from three studies that compared a longer duration of IPT to the standard six-month course. Continuous versus a six-month course of IPT reduced TB incidence. Consistent with other studies, this benefit was clear in people with a positive tuberculin skin test (TST) at baseline but smaller and not significant in people with a negative TST. This meta-analysis also found a reduction in mortality among people with a positive TST receiving continuous IPT, primarily based on data from the study in Botswana. This is notable because most previous trials of IPT versus control have not demonstrated a mortality benefit. Most trials of short-course IPT were undertaken in the pre-antiretroviral therapy (ART) era, when all-cause mortality was very high. In the Botswana study, ART was available and will have reduced HIV-associated mortality among all participants, which may have allowed a difference in TB-specific mortality to become evident.

Adverse events were very similar between the continuous versus short course IPT groups in the studies from Botswana and India. However, in the South African study, adverse events were more common in the continuous IPT group, as were temporary or permanent discontinuations due to adverse events. Abnormal liver function tests were particularly common, but it is not clear how many of these were symptomatic and thus would be detected in a programme where liver function is not routinely monitored.

These data support WHO recommendations for continuous IPT for HIV-positive people in settings where TB transmission is common. What is not clear is how to define settings where TB transmission is common enough for this recommendation to be applied. 

Africa, Asia
Botswana, India, South Africa
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Current dosages for treatment of TB in children living with HIV may be sub-optimal

Low serum concentrations of rifampicin and pyrazinamide associated with poor treatment outcomes in children with tuberculosis related to HIV status.

Ramachandran G, Kumar AK, Kannan T, Bhavani PK, Kumar RS, Gangadevi NP, Banurekha VV, Sudha V, Venkatesh S, Ravichandran N, Kalpana S, Mathevan G, Sanjeeva GN, Agarwal D, Swaminathan S. Pediatr Infect Dis J. 2016 Jan 27. [Epub ahead of print]

Objectives: To compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between HIV-infected and uninfected children with TB and correlate it with TB treatment outcome.

Methods: HIV-uninfected (n = 84) and HIV-infected (n = 77) children with TB receiving standard thrice weekly treatment, were recruited from six hospitals in India. Semi-intensive pharmacokinetic sampling was performed during intensive phase of TB treatment after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography (HPLC). INH acetylator status was determined and nutritional assessment was done. Children were followed up and treatment outcomes noted.

Results: Children with HIV & TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1µg/ml; p<0.001) and exposure (AUC0-8) (10.4 vs. 23.4 µg/ml.h; p<0.001) than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs 29%; p < 0.001) and underweight (73% vs 38%; p < 0.001) compared to children with TB. Combining both groups, RMP Cmax (p = 0.001; AOR = 1.437; 95% CI: 1.157 - 1.784) and PZA Cmax (p = 0.027; AOR = 1.041; 95% CI: 1.005 - 1.079) significantly influenced treatment outcome.

Conclusions: HIV infection was associated with lower Cmax of RMP and INH and AUC0-8 of RMP. Over 90% of children in both groups had sub-therapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV & TB.

Abstract access 

Editor’s notes: Determinants of outcomes in childhood TB are relatively understudied compared to outcomes among adults. The authors have conducted a detailed pharmacokinetic study in Indian children to examine the association of HIV and anthropometric indices with the peak concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide PZA). Despite the small sample size they demonstrated that HIV-positive children fared worse in terms of achieving therapeutic levels of INH and RMP, but also that only 10% of all children achieved therapeutic levels of RMP, irrespective of HIV status and malnutrition. Similar investigations of RMP pharmacokinetics in other very recent studies (Arya et al. 2015 IJTLD, Bekker et al. 2015 Antimicrob Agents Chemother) found overall sub-therapeutic levels and also called, as the authors do, for a review of paediatric dosages in TB programmes.  Kwara et al. (2015 J Pediatric Infect Dis Soc) also observed the association of levels with HIV.

The data seem to provide scientific consensus that, assuming the recommended therapeutic serum levels are appropriate, under the current WHO TB treatment guidelines; children and infants are not receiving optimal chemotherapy for TB. The data suggest that dosages should be reviewed and that particularly in settings where a high proportion of children treated for TB are HIV-positive, that HIV-positive children may require further alterations to the schedules to ensure adequate levels for treatment success. 

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TB still responsible for large proportion of admissions and in-patient deaths among people living with HIV

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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Depression in people living with HIV – importance of family dynamics

The importance of the family: a longitudinal study of the predictors of depression in HIV patients in South Africa.

Wouters E, Masquillier C, le Roux Booysen F. AIDS Behav. 2016 Jan 18. [Epub ahead of print]

As a chronic illness, HIV/AIDS requires life-long treatment adherence and retention and thus sufficient attention to the psychosocial dimensions of chronic disease care in order to produce favourable antiretroviral treatment (ART) outcomes in a sustainable manner. Given the high prevalence of depression in chronic HIV patients, there is a clear need for further research into the determinants of depression in this population. In order to comprehensively study the predictors of depressive symptoms in HIV patients on ART, the socio-ecological theory postulates to not only incorporate the dominant individual-level and the more recent community-level approaches, but also incorporate the intermediate, but crucial family-level approach. The present study aims to extend the current literature by simultaneously investigating the impact of a wide range individual-level, family-level and community-level determinants of depression in a sample of 435 patients enrolled in the Free State Province of South Africa public-sector ART program. Structural equation modeling is used to explore the relationships between both latent and manifest variables at two time points. Besides a number of individual-level correlates—namely education, internalized and external stigma, and avoidant and seeking social support coping styles—of depressive symptoms in HIV patients on ART, the study also revealed the important role of family functioning in predicting depression. While family attachment emerged as the only factor to continuously and negatively impact depression at both time points, the second dimension of family functioning, changeability, was the only factor to produce a negative cross-lagged effect on depression. The immediate and long-term impact of family functioning on depression draws attention to the role of family dynamics in the mental health of people living with HIV/AIDS. In addition to individual-level and community-based factors, future research activities should also incorporate the role of the family context in research into the mental health of HIV patients, as our results demonstrate that the familial context in which a person with HIV on ART resides is inextricably interconnected with his/her health outcomes.

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Editor’s notes: Effective treatment in the form of antiretroviral therapy now exists for HIV. This means that people living with HIV can have a near-normal life expectancy, provided treatment is started early and adherence to treatment is good. In many settings, including low-income countries, HIV has transitioned from being a terminal illness to a controllable chronic disease. And this brings new challenges for health care providers. As with many chronic illnesses that require lifelong treatment, a diagnosis of HIV can induce depressive symptoms. People living with HIV face a number of additional challenges including stigma, which can impact negatively on mental health. Furthermore, in high HIV prevalence areas people are likely to have witnessed AIDS-related deaths of friends and family. The challenge of providing additional psychosocial care to a growing population of people living with HIV is daunting. This is especially true in resource-poor settings where mental health care services are already stretched. There is a need for research to understand the determinants of depression in order to inform development of appropriate programmes.

This study contributes data on a range of family-level determinants in addition to individual-level and community-level determinants for depression in HIV-positive people. Few studies have focussed on depression in HIV-positive people and the impact of family functioning. Unlike this study, those that have were not conducted in high HIV prevalence, resource-poor settings. The investigators report that family attachment was the only factor that continuously impacted on depression in this population at two different time points. This highlights the role of family dynamics in the mental health and well-being of people living with HIV. Further research that incorporates in-depth qualitative methods is necessary, not only to confirm these findings but to also broaden our understanding of the determinants for depression.  

South Africa
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