Articles tagged as "Comorbidity"

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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Time to consider older adults on ART

Risk factors for mortality during antiretroviral therapy in older populations in resource-limited settings.

O'Brien D, Spelman T, Greig J, McMahon J, Ssonko C, Casas E, Mesic A, Du Cros P, Ford N. J Int AIDS Soc. 2016 Jan 14;19(1):20665. doi: 10.7448/IAS.19.1.20665. eCollection 2016.

Introduction: An increasing proportion of adult patients initiating antiretroviral therapy (ART) in resource-limited settings are aged >50 years. Older populations on ART appear to have heightened risk of death, but little is known about factors influencing mortality in this population.

Methods: We performed a retrospective observational multisite cohort study including all adult patients (≥15 years) initiating ART between 2003 and 2013 in programmes supported by Medecins Sans Frontieres across 12 countries in Asia, Africa and Europe. Patients were stratified into two age groups, >50 years and 15 to 50 years. A Cox proportional hazards model was used to explore factors associated with mortality.

Results: The study included 41 088 patients: 2591 (6.3%) were aged >50 years and 38 497 (93.7%) were aged 15 to 50 years. The mortality rate was significantly higher in the age group >50 years [367 (14.2%) deaths; mortality rate 7.67 deaths per 100 person-years (95% confidence interval, CI: 6.93 to 8.50)] compared to the age group 15 to 50 years [3788 (9.8%) deaths; mortality rate 4.18 deaths per 100 person-years (95% CI: 4.05 to 4.31)], p<0.0001. Higher CD4 levels at baseline were associated with significantly reduced mortality rates in the 15 to 50 age group but this association was not seen in the >50 age group. WHO Stage 4 conditions were more strongly associated with increased mortality rates in the 15 to 50 age group compared to populations >50 years. WHO Stage 3 conditions were associated with an increased mortality rate in the 15 to 50 age group but not in the >50 age group. Programme region did not affect mortality rates in the >50 age group; however being in an Asian programme was associated with a 36% reduced mortality rate in populations aged 15 to 50 years compared to being in an African programme. There was a higher overall incidence of Stage 3 WHO conditions in people >50 years (12.8/100 person-years) compared to those 15 to 50 years (8.1/100 person-years) (p<0.01). The rate of Stage 4 WHO conditions was similar (5.8/100 versus 6.1/100 respectively, p=0.52). Mortality rates on ART associated with the majority of specific WHO conditions were similar between the 15 to 50 and >50 age groups.

Conclusions: Older patients on ART in resource-limited settings have increased mortality rates, but compared to younger populations this appears to be less influenced by baseline CD4 count and WHO clinical stage. HIV treatment programmes in resource-limited settings need to consider risk factors associated with mortality on ART in older populations, which may differ to those related to younger adults.

Abstract Full-text [free] access

Editor’s notes: This article reports on a retrospective multisite cohort analysis that examined mortality rates and factors associated with mortality on ART for older individuals (> 50 years). The authors found that mortality was nearly two times greater in populations aged >50 years compared with people aged 15 to 50 years.

Contrary to other recent research, they did not find that the effect of age on mortality was stronger at lower CD4 cell counts. However, the analysis used pooled data from very diverse settings, with the great majority of patients (77%) from Asian programmes, and only 22% from Africa (and from nine different countries). This makes it difficult to tease out risk factors for mortality.

Interestingly they found that being in an Asian programme was associated with a 36% reduction in mortality (aHR: 0.64, 95%CI 0.59-0.69) among populations between 15 and 50 years compared to being in an African programme. The authors suggest that this might be due to a lower incidence of co-morbidities including opportunistic infections in Asian populations below 50 years compared to African populations.

As little is known about what it is like living with HIV for older people in resource-limited settings, the authors conclude with suggesting further social science research to address this issue. 

Africa, Asia, Europe
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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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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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HIV contributes to stroke among young people

HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: A case-control study.

Benjamin LA, Corbett EL, Connor MD, Mzinganjira H, Kampondeni S, Choko A, Hopkins M, Emsley HC, Bryer A, Faragher B, Heyderman RS, Allain TJ, Solomon T. Neurology. 2015 Dec 18. pii: 10.1212/WNL.0000000000002278. [Epub ahead of print]

Objective: To investigate HIV, its treatment, and hypertension as stroke risk factors in Malawian adults.

Methods: We performed a case-control study of 222 adults with acute stroke, confirmed by MRI in 86%, and 503 population controls, frequency-matched for age, sex, and place of residence, using Global Positioning System for random selection. Multivariate logistic regression models were used for case-control comparisons.

Results: HIV infection (population attributable fraction [PAF] 15%) and hypertension (PAF 46%) were strongly linked to stroke. HIV was the predominant risk factor for young stroke (≤45 years), with a prevalence of 67% and an adjusted odds ratio (aOR) (95% confidence interval) of 5.57 (2.43-12.8) (PAF 42%). There was an increased risk of a stroke in patients with untreated HIV infection (aOR 4.48 [2.44-8.24], p < 0.001), but the highest risk was in the first 6 months after starting antiretroviral therapy (ART) (aOR 15.6 [4.21-46.6], p < 0.001); this group had a lower median CD4+ T-lymphocyte count (92 vs 375 cells/mm3, p = 0.004). In older participants (HIV prevalence 17%), HIV was associated with stroke, but with a lower PAF than hypertension (5% vs 68%). There was no interaction between HIV and hypertension on stroke risk.

Conclusions: In a population with high HIV prevalence, where stroke incidence is increasing, we have shown that HIV is an important risk factor. Early ART use in immunosuppressed patients poses an additional and potentially treatable stroke risk. Immune reconstitution inflammatory syndrome may be contributing to the disease mechanisms.

Abstract Full-text [free] access

Editor’s notes: Stroke incidence is increasing across sub-Saharan Africa. Globally, hypertension accounts for most of the strokes. However, in sub-Saharan Africa, stroke is not uncommon among younger people, among whom the prevalence of hypertension is low. Therefore other factors may play a role.

This article reports on a case-control study with prospective recruitment of cases and community controls, examining the role of HIV, antiretroviral therapy, and the interaction between HIV and hypertension as risk factors for stroke in a setting with high HIV prevalence.

The investigators confirmed 86% of their cases with brain imaging, and found that the majority (78%) had findings consistent with ischemic stroke. Not surprisingly they found that overall, hypertension accounted for about half (46%) of the stroke cases. Interestingly only one-quarter of all people with hypertension in the study (cases and controls) were on hypertensive treatment.

However, among younger people (≤45 years) with stroke, HIV infection was the most important risk factor and accounted for 42% of the cases. HIV-positive people experienced the greatest risk of stroke during their first six months after ART initiation.

The HIV-positive stroke cases had a lower CD4 cell count compared to HIV-positive controls on the same duration of ART. Immunosuppression is a risk factor for immune constitution inflammatory syndrome (IRIS), and IRIS could thus be a plausible mechanism of stroke among people initiating ART.

The results of this study reinforce the need to start ART before people have advanced immunosuppression, which will reduce IRIS-associated morbidity. The latest WHO guidelines, ‘Treat all’, which recommend starting all HIV-positive people on antiretroviral therapy as soon after diagnosis as possible, have the potential to contribute to this.  

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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
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
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
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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