Articles tagged as "Comorbidity"

Non-communicable diseases and co-morbidities – the flip side of successful ART programmes?

Editor’s notes: As the population of people living with HIV grows older and lives longer, the importance of non-communicable diseases is increasing.  Several studies this month explored various aspects of this intersection.

An encouraging study from Spain by Sorigué M et al., analysed the outcomes of patients with advanced stage Hodgkin’s lymphoma, a relatively common cancer both among people living with HIV and the HIV-negative population. The authors showed that, in the era of combined antiretroviral therapy, the complete response rate and ten year survival were not significantly different among people living with HIV (89% and 73%) and HIV negative people (91% and 68%).

Another broadly encouraging study from Ireland by Tinago W et al., followed up 384 people (176 living with HIV) to determine changes over three years in their bone mineral density (BMD).  BMD was somewhat lower in the people living with HIV, despite the group being younger on average.  As expected, BMD gradually fell with increasing age but the rate of bone loss was no different between people living with HIV and HIV negative people.  88% of the people living with HIV were on ART at the start of the study period.  Not having started ART among people living with HIV was associated with lower BMD and people who had started more recently showed the largest declines in BMD.  This suggests (as has previously been shown in cohorts of people living with HIV) that after an initial loss in BMD, the rate of loss stabilizes and is similar to HIV-negative people.  Interestingly, the authors did not show that overall exposure to tenofovir disproxil fumarate (TDF) was particularly associated with greater BMD loss over the course of follow up, despite several previous randomized trials confirming that TDF does cause BMD loss when it is started.

While on the subject of TDF, this month saw two important regulatory trials of tenofovir alafenamide (TAF), sponsored by the manufacturers Gilead Sciences.  630 people living with HIV on treatment with rilpivirine, emtricitabine and TDF whose viral load was supressed, were randomly allocated to remain on the same regimen or to swap the TDF for TAF.  TAF is a pro-drug, that reduces the plasma concentrations of tenofovir and is therefore expected to reduce the renal and bone toxicities associated with TDF while still delivering active drug to the cells where it is needed.  One year later, viral suppression was very similar in the two groups (94%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 6% vs. 12% having some side effects in the TAF and TDF arms respectively [Orkin C and colleagues].

A related study by DeJesus E et al. with the same design was conducted among people taking efavirenz, emtricitabine and tenofovir, one of the most common first line regimens throughout the world. In this trial the efavirenz was switched to rilpivirine and the TDF to TAF.  875 people living with HIV whose viral load was supressed were randomized and after one year viral suppression was very similar in the two groups (90-92%).  There was also no significant difference seen in the side effects over this one year period, with no serious adverse events and 13% vs. 10% having some side effects in the rilpivirine -TAF and efavirenz-TDF arms respectively.

Returning to co-morbidities and non-communicable diseases, a study by Rodríguez-Arbolí E and colleagues in rural Tanzania has shown that 11.6% of people living with HIV who had not yet started ART had raised blood pressure.  A further 9.6% develop raised blood pressure during follow up, an incidence of 12 per 100 person years. The risk factors for developing hypertension were those well recognized in HIV-negative populations (age, renal disease and being overweight) and not specifically related to HIV infection, ART or immunological status.  The authors recommend integration of non-communicable disease screening and management into HIV care clinics but a larger conclusion might be to improve management of hypertension more generally, as it affects both people living with HIV and people without.

In contrast, a study by Pollack TM et al. from Viet Nam shows that smoking tobacco is associated with a higher viral load among people living with HIV presenting for ART.  As would be expected, other predictors of more advanced HIV disease such as lower CD4 counts and lower BMI and prior TB were all associated with a higher viral load at presentation.  Male sex was also significantly associated with a higher viral load.  The authors point out various other studies from Cameroon and the US that have shown similar and related interactions between smoking tobacco, viral load at presentation or viral load suppression or rebound on ART treatment.  Other studies in the US have not found this association.  One of the challenges is to separate behavioural factors that might be confounders – perhaps people who smoke are more likely to present late.  In this study there was not a clear dose response.  People who smoked more than ten cigarettes per day were actually somewhat less likely in this sample to have a higher viral load than people who smoked 1-10 cigarettes per day, but the numbers were too small to make statistically significant claims.  The authors suggest that oxidative stress and induction of the cytochrome P450 (CYP) pathway could explain the mechanism of smoking-related increased VL among HIV positive individuals.  While the study cannot prove cause and effect, there are already many reasons to promote tobacco cessation among people living with HIV and this may be an additional one.

The D:A:D study is a major prospective cohort that follows more than 49 000 people living with HIV in Europe, Australia and the USA.  Among the cohort, more than 4000 have developed chronic renal impairment.  A study by Ryom L et al. this month examined whether there was improvement, stabilisation or progression of renal impairment in the 2006 individuals who had additional measurements 2-3 years after renal impairment was first noted and explored risk factors for each.  On the one hand, they show that some ARVs (notably TDF and ritonavir-boosted atazanovir) are associated with worse renal outcomes, but on the other hand, they demonstrate that after stopping these nephrotoxic medicines, the kidneys recover or at least do not deteriorate further.  Once again, traditional risk factors (older age, high blood pressure and diabetes) are also important risk factors for the kidneys of people living with HIV.  As the population of people living with HIV gets older and lives longer, HIV care and traditional non-communicable disease management must overlap and coordinate.

HIV-infection has no prognostic impact on advanced-stage Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine and dacarbazine.

Sorigué M, García O, Tapia G, Baptista MJ, Moreno M, Mate JL, Sancho JM, FeliuE, Ribera JM, Navarro JT. AIDS. 2017 Mar 29. doi: 10.1097/QAD.0000000000001487. [Epub ahead of print]

Objective: Classical Hodgkin lymphoma (cHL) is a non-AIDS-defining cancer with good response to chemotherapy in the combined antiretroviral therapy (cART) era. The aim of the study was to compare the characteristics, the response with treatment and survival of advanced-stage cHL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) between cART-treated HIV-positive and HIV-negative patients.

Design and methods: We retrospectively analyzed advanced-stage cHL patients from a single institution, uniformly treated with ABVD. All HIV-positive patients received cART concomitantly with ABVD.

Results: A total of 69 patients were included in the study: 21 were HIV-positive and 48 were HIV-negative. HIV-positive patients had more aggressive features at cHL diagnosis, such as worse performance status, more frequent bone marrow involvement and mixed cellularity histologic subtype. There were no differences in complete response rate (89% in HIV-positive vs. 91% in HIV-negative), P = 1; disease-free survival 10-year disease-free survival 70% (41-99%) vs. 74% (57-91%), P = 0.907 and overall survival (OS) 10-year OS 73% (95% confidence interval52-94%) vs. 68% (51-85%), P = 0.904. On multivariate analysis, HIV infection did not correlate with worse OS.

Conclusion: Although HIV-positive patients with cHL had more aggressive baseline features in this series, there were no differences in response rate or survival between HIV-positive and HIV-negative patients.

Abstract access 

Predictors of longitudinal change in bone mineral density in a cohort of HIV-positive and negative patients.

Tinago W, Cotter AG, Sabin CA, Macken A, Kavanagh E, Brady JJ, McCarthy G,Compston J, Mallon PW; HIV UPBEAT Study Group.225. AIDS. 2017 Mar 13;31(5):643-652. doi: 10.1097/QAD.0000000000001372.

Objective: Although low bone mineral density (BMD) is prevalent in HIV, changes in BMD over time remain unclear. We aimed to compare rates of, and factors associated with, BMD change between HIV-positive and HIV-negative patients.

Methods: In a prospective, 3-year cohort, HIV-positive and HIV-negative patients provided annual demographic and clinical data, fasting bloods, and dual x-ray absorptiometry. Using longitudinal mixed models we compared and determined predictors of rate of change in BMD.

Results: Of 384 study participants (45.8% HIV positive), 120 contributed two and 264 contributed three BMD measurements. Those with HIV were younger [median interquartile range 39 (34-46) vs. 43 (35-50) years; P = 0.04], more often men (61 vs. 46%; P = 0.003), and less likely Caucasian (61 vs. 82%; P < 0.001).Although BMD was lower in those with HIV, BMD declined in both groups, with nonsignificant between-group difference in rate of BMD change over time. Within the HIV group, starting antiretroviral therapy (ART) within 3 months of enrolment was associated with greater BMD decline at all anatomical sites (all P < 0.001). Age more than 30 years, Caucasian ethnicity, and not being on ART during follow-up were associated with greater decline and higher parathyroid hormone associated with a smaller decline in BMD at the femoral neck. We found no association between BMD change and exposure to tenofovir disoproxil fumarate or protease inhibitors.

Conclusion: We observed no difference in rate of BMD decline regardless of HIV status and in HIV-positive patient, having started ART within the previous 3 months was the only factor associated with greater BMD decline at all three sites.

Abstract access 

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

Orkin C,  DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Vandercam B, de Wet J, Rockstroh J, Lazzarin A, Rijnders B, Podzamczer D, Thalme A, Stoeckle M, Porter D, Liu HC, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30031-0. doi:10.1016/S2352-3018(17)30031-0. [Epub ahead of print]

Background: Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per ml) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 ml/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per ml of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with clinicaltrials.gov, number NCT01815736.

Findings: Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per ml HIV-1 RNA (difference -0·3%, 95·001% CI-4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20(6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

DeJesus E, Ramgopal M, Crofoot G, Ruane P, LaMarca A, Mills A, Martorell CT, de Wet J, Stellbrink HJ, Molina JM, Post FA, Valero IP, Porter D, Liu Y, Cheng A, Quirk E, SenGupta D, Cao H. Lancet HIV. 2017 Mar 1. pii: S2352-3018(17)30032-2. doi:10.1016/S2352-3018(17)30032-2. [Epub ahead of print]

Background: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine,and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Methods: In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned(1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine(200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226.

Findings: Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group.

Interpretation: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.

Abstract access 

Incidence and risk factors for hypertension among HIV patients in rural Tanzania - A prospective cohort study.

Rodríguez-Arbolí E, Mwamelo K, Kalinjuma AV, Furrer H, Hatz C, Tanner M, Battegay M, Letang E; KIULARCO Study Group. PLoS One. 2017 Mar 8;12(3):e0172089. doi: 10.1371/journal.pone.0172089.eCollection 2017.

Introduction: Scarce data are available on the epidemiology of hypertension among HIV patients in rural sub-Saharan Africa. We explored the prevalence, incidence and risk factors for incident hypertension among patients who were enrolled in a rural HIV cohort in Tanzania.

Methods: Prospective longitudinal study including HIV patients enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2013 and 2015. Non-ART naïve subjects at baseline and pregnant women during follow-up were excluded from the analysis. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two consecutive visits. Cox proportional hazards models were used to assess the association of baseline characteristics and incident hypertension.

Results: Among 955 ART-naïve, eligible subjects, 111 (11.6%) were hypertensive at recruitment. Ten women were excluded due to pregnancy. The remaining 834 individuals contributed 7967 person-months to follow-up (median 231 days, IQR 119-421) and 80 (9.6%) of them developed hypertension during a median follow-up of 144 days from time of enrolment into the cohort [incidence rate 120.0 cases/1000 person-years, 95% confidence interval (CI) 97.2-150.0]. ART was started in 630 (75.5%) patients, with a median follow-up on ART of 7 months (IQR 4-14). Cox regression models identified age [adjusted hazard ratio (aHR) 1.34 per 10 years increase, 95% CI 1.07-1.68, p = 0.010], body mass index (aHR per 5 kg/m2 1.45, 95% CI 1.07-1.99, p = 0.018) and estimated glomerular filtration rate (aHR < 60 versus ≥ 60 ml/min/1.73 m2 3.79, 95% CI 1.60-8.99, p = 0.003) as independent risk factors for hypertension development.

Conclusions: The prevalence and incidence of hypertension were high in our cohort. Traditional cardiovascular risk factors predicted incident hypertension, but no association was observed with immunological or ART status. These data support the implementation of routine hypertension screening and integrated management into HIV programmes in rural sub-Saharan Africa.

Abstract  Full-text [free] access

Cigarette smoking is associated with high HIV viral load among adults presenting for antiretroviral therapy in Vietnam.

Pollack TM, Duong HT, Pham TT, Do CD, Colby D. PLoS One. 2017 Mar 7;12(3):e0173534. doi: 10.1371/journal.pone.0173534.eCollection 2017.

High HIV viral load (VL >100 000 cp/ml) is associated with increased HIV transmission risk, faster progression to AIDS, and reduced response to some antiretroviral regimens. To better understand factors associated with high VL, we examined characteristics of patients presenting for treatment in Hanoi, Vietnam. We examined baseline data from the Viral Load Monitoring in Vietnam Study, a randomized controlled trial of routine VL monitoring in a population starting antiretroviral therapy (ART) at a clinic in Hanoi. Patients with prior treatment failure or ART resistance were excluded. Characteristics examined included demographics, clinical and laboratory data, and substance use. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Out of 636 patients, 62.7% were male, 72.9% were ≥30 years old, and 28.3% had a history of drug injection. Median CD4 was 132cells/mm3, and 34.9% were clinical stage IV. Active cigarette smoking was reported by 36.3% with 14.0% smoking >10 cigarettes per day. Alcohol consumption was reported by 20.1% with 6.1% having ≥5 drinks per event. Overall 53.0% had a VL >100 000 cp/ml. Male gender, low body weight, low CD4 count, prior TB, and cigarette smoking were associated with high VL. Those who smoked 1-10 cigarettes per day were more likely to have high VL (aOR = 1.99, 95% CI = 1.15-3.45), while the smaller number of patients who smoked >10 cigarettes per day had a non-significant trend toward higher VL (aOR = 1.41, 95% CI = 0.75-2.66). Alcohol consumption was not significantly associated with high VL. Tobacco use is increasingly recognized as a contributor to premature morbidity and mortality among HIV-infected patients. In our study, cigarette smoking in the last 30 days was associated with a 1.5 to 2-fold higher odds of having an HIV VL >100 000 cp/ml among patients presenting for ART. These findings provide further evidence of the negative effects of tobacco use among HIV-infected patients.

Abstract  Full-text [free] access 

Predictors of eGFR progression, stabilisation or improvement after chronic renal impairment in HIV-positive individuals.

Ryom L, Mocroft A, Kirk O, Reiss P, Ross M, Smith C, Moranne O, Morlat P, Fux CA, Sabin C, Phillips A, Law M, Lundgren JD; D:A:D study group. AIDS. 2017 Mar 28. doi: 10.1097/QAD.0000000000001464. [Epub ahead of print]

Objectives: The objectives of this analysis were to investigate predictors of progression, stabilisation or improvement in eGFR after development of chronic renal impairment (CRI) in HIV-positive individuals.

Design: Prospective observational study.

Methods: D:A:D study participants progressing to CRI defined as confirmed, ≥ 3 months apart, eGFR ≤70  mL/min/1.73m were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared to the median eGFR defining CRI, and changes were grouped into: improvement (>+10 mL/min/1.73m), stabilisation (-10 to +10 mL/min/1.73m) and progression (<-10 mL/min/1.73m). Adjusted polynomial regression models assessed odds of better eGFR outcomes after CRI, assuming eGFR improvement is better than stabilisation which in turn is better than progression.

Results: Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilised and 12% progressed. Individuals remaining on TDF or boosted atazanavir (ATV/r) 24 months post-CRI had worse eGFR outcomes compared to those unexposed (TDF: 0.47 [0.35-0.63], ATV/r: 0.63 [0.48-0.82]). Individuals off TDF for 12-24 months (0.75 [0.50-1.13]) or off ATV/r for >12 months (1.17 [0.87-1.57]) had similar eGFR outcomes as those unexposed to these ARVs. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes.

Conclusion: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer-term eGFR outcomes as in those unexposed suggesting these drug-associated eGFR declines may be halted or reversed after their cessation.

Abstract access  

Comorbidity, HIV Treatment
Africa, Asia, Europe, Northern America, Oceania
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Infectious co-morbidities – why are people still dying of advanced HIV infections?

Editor’s notes: Tuberculosis remains the biggest reported killer of people living with HIV.  Studies from Guangxi, China and Nigeria examine risk factors for tuberculosis.  In the Chinese study, Cui Z and colleagues found almost one in six of 1019 people receiving care for HIV had active tuberculosis.  The risk factors that they found when comparing these 160 people with tuberculosis to matched controls living with HIV but without tuberculosis were well-known (low CD4 cell count, smoking and non-use of ART).  Long duration of HIV infection was also independently associated with developing tuberculosis, emphasising the need for tuberculosis specific measures in addition to ART.  The authors recommend standard approaches that need to be strengthened (active screening and case-finding with early initiation of ART; isoniazid preventive therapy and better infection control).  The most extraordinary statistic is how much higher the rate of tuberculosis is among this group of people receiving HIV care than it is among the general population of Guangxi.  173 times higher is pretty impressive!

The Pathmanathan I et al. study in Nigeria, carried out as part of a broader analysis of the outcomes of a nationally representative sample of people taking ART, is more optimistic.  The incidence rate for tuberculosis once people started on ART was 0.57 per 100 person years, which compares quite favourably with the estimated incidence for Nigeria from the WHO Global Tuberculosis 2016 report [link] of 0.32 per 100 person years.  Furthermore, most of the incident tuberculosis occurred soon after starting ART and (as might be expected) was most common in people with low CD4 count; previous tuberculosis or suspected but not diagnosed tuberculosis on starting ART.  Once people’s CD4 count was above 200 cells per ml, the incidence rate was 0.29 per 100 person-years.  This is encouraging, as it suggests that a good ART programme could have a significant impact on the overall risk of tuberculosis.  The aim of collaborative tuberculosis and HIV programme efforts must be to find people living with HIV before they are so immunocompromised.  In this study, the average CD4 count at enrolment was less than 200 cells per ml and around 5% of people already had tuberculosis at that time.

Late HIV diagnosis was also the subject of a study from Jiangsu province in China.  Hu H and colleagues looked at the trends in HIV testing and presentation to care before the CD4 count fell below 350 cells per ml.  From 2011-2014 in cross-sectional annual community based surveys among around 2500 men who have sex with men (MSM), there was a modest decline in the proportion who had had an HIV test within the last 12 months from 60% to 53%, and late presentation remained stable around 40%.  We have to shift from this plateau and the authors point out that HIV self-tests seem highly acceptable to MSM in China and that social media and internet based advocacy might also help.

There is increasing interest in co-infections with hepatitis B and C viruses in people living with HIV.  Hepatitis B is widespread in many countries in sub-Saharan Africa with “horizontal” transmission occurring in childhood.  Vaccination is now included as part of some countries programmes on expanded immunisation.  Co-infection with HIV and Hepatitis B leads to more rapid progression of liver damage and to liver cancer. Seremba E and colleagues tested stored sera from people living with HIV in the Rakai community and found that around half had already been infected with hepatitis B (in line with the high prevalence of infection in children).  During the follow up samples from people who were hepatitis B negative, new infections with hepatitis B occurred in 39 individuals, giving an incidence rate of 1.2 per 100 person years.  While hepatitis B vaccine is recommended for people living with HIV who are not infected, this study shows that ART is also protective, particularly if it contains lamivudine or tenofovir.  So this may be an added benefit of the wider scale-up of ART.

Despite advance in ART, too many people still die with HIV-associated infections that are only seen at low CD4 cell counts.  An important example is cryptococcal meningitis, which causes an insidious onset of symptoms. By the time patients are seen at the hospital with severe headache and signs of raised intracranial pressure it is often too late to prevent them from dying. This is because the best medicines (liposomal amphotericin and flucytosine) are expensive and often not available.  So WHO recommends pre-emptive treatment for people who are first seen at the health service with CD4 counts less than 100 cells per ml and with cryptococcal antigen (CRAG) detectable in the blood.  A modelling study by Ramachandran A et al. from Uganda and the US considered the likely costs and benefits of using a new lateral flow assay for CRAG for people living with HIV with a low CD4 count, with pre-emptive treatment with fluconazole for people found to be CRAG-positive. The results, including various sensitivity tests, are strongly in favour of widespread implementation of this strategy. The authors calculate that it would cost Uganda around US$650 000 per year and would avert more than a thousand deaths.  Like the tuberculosis discussions above, the real aim is to prevent people living with HIV reaching the stage where “old-fashioned” opportunistic infections can cause such misery.  However in the medium term, we are likely to continue to see many people presenting late in the course of their infections, and CRAG (and tuberculosis) screening and management are key ways to prevent mortality.

Risk factors associated with Tuberculosis (TB) among people living with HIV/AIDS: A pair-matched case-control study in Guangxi, China.

Cui Z, Lin M, Nie S, Lan R. PLoS One. 2017 Mar 30;12(3):e0173976. doi:10.1371/journal.pone.0173976.eCollection 2017.

Background: As one of the poorest provinces in China, Guangxi has a high HIV and TB prevalence, with the annual number of TB/HIV cases reported by health department among the highest in the country. However, studies on the burden of TB-HIV co-infection and risk factors for active TB among HIV-infected persons in Guangxi have rarely been reported.

Objective: To investigate the risk factors for active TB among people living with HIV/AIDS in Guangxi Zhuang autonomous region, China.

Methods: A surveillance survey was conducted of 1019 HIV-infected patients receiving care at three AIDS prevention and control departments between 2013 and 2015. We investigated the cumulative prevalence of TB during 2 years. To analyze risk factors associated with active TB, we conducted a 1:1 pair-matched case-control study of newly reported active TB/HIV co-infected patients. Controls were patients with HIV without active TB, latent TB infection or other lung disease, who were matched with the case group based on sex and age (± 3 years).

Results: A total of 1019 subjects were evaluated. 160 subjects (15.70%) were diagnosed with active TB, including 85 clinically diagnosed cases and 75 confirmed cases. We performed a 1:1 matched case-control study, with 82 TB/HIV patients and 82 people living with HIV/AIDS based on surveillance site, sex and age (±3) years. According to multivariate analysis, smoking (OR = 2.996, 0.992-9.053), lower CD4+ T-cell count (OR = 3.288, 1.161-9.311), long duration of HIV-infection (OR = 5.946, 2.221-15.915) and non-use of ART (OR = 7.775, 2.618-23.094) were independent risk factors for TB in people living with HIV/AIDS.

Conclusion: The prevalence of active TB among people living with HIV/AIDS in Guangxi was 173 times higher than general population in Guangxi. It is necessary for government to integrate control planning and resources for the two diseases. Medical and public health workers should strengthen health education for TB/HIV prevention and treatment and promote smoking cessation. Active TB case finding and early initiation of ART is necessary to minimize the burden of disease among patients with HIV, as is IPT and infection control in healthcare facilities.

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Incidence and predictors of tuberculosis among HIV-infected adults after initiation of antiretroviral therapy in Nigeria, 2004-2012.

Pathmanathan I, Dokubo EK, Shiraishi RW, Agolory SG, Auld AF, Onotu D, Odafe S, Dalhatu I, Abiri O, Debem HC, Bashorun A, Ellerbrock T. PLoS One. 2017 Mar 10;12(3):e0173309. doi: 10.1371/journal.pone.0173309.eCollection 2017.

Background: Nigeria had the most AIDS-related deaths worldwide in 2014 (170 000), and 46% were associated with tuberculosis (TB). Although treatment of people living with HIV (PLHIV) with antiretroviral therapy (ART) reduces TB-associated morbidity and mortality, incident TB can occur while on ART. We estimated incidence and characterized factors associated with TB after ART initiation in Nigeria.

Methods: We analyzed retrospective cohort data from a nationally representative sample of adult patients on ART. Data were abstracted from 3496 patient records, and analyses were weighted and controlled for a complex survey design. We performed domain analyses on patients without documented TB disease and used a Cox proportional hazard model to assess factors associated with TB incidence after ART.

Results: At ART initiation, 3350 patients (95.8%) were not receiving TB treatment. TB incidence after ART initiation was 0.57 per 100 person-years, and significantly higher for patients with CD4<50/μL (adjusted hazard ratio [AHR]:4.2, 95% confidence interval [CI]: 1.4-12.7) compared with CD4≥200/μL. Patients with suspected but untreated TB at ART initiation and those with a history of prior TB were more likely to develop incident TB (AHR: 12.2, 95% CI: 4.5-33.5 and AHR: 17.6, 95% CI: 3.5-87.9, respectively).

Conclusion: Incidence of TB among PLHIV after ART initiation was low, and predicted by advanced HIV, prior TB, and suspected but untreated TB. Study results suggest a need for improved TB screening and diagnosis, particularly among high-risk PLHIV initiating ART, and reinforce the benefit of early ART and other TB prevention efforts.

Abstract  Full-text [free] access 

Trends in late HIV diagnosis among men who have sex with men in Jiangsu province, China: Results from four consecutive community-based surveys, 2011-2014.

Hu H, Yan H, Liu X, Xu X, Xu J, Qiu T, Shi LE, Fu G, HuanX, McFarland W, Wei C). PLoS One. 2017 Mar 9;12(3):e0172664. doi:10.1371/journal.pone.0172664.eCollection 2017.

Objectives: To examine trends in HIV testing, late HIV diagnosis and associated factors among men who have sex with men (MSM) in Jiangsu province, China.

Methods: Four consecutive community-based cross-sectional surveys were conducted among MSM from 2011 to 2014 in eight cities in the province. Participants were recruited from MSM venues and via the internet. HIV bio-behavioral surveys were conducted to collect demographic and behavioral data and measure HIV infection. HIV-infected participants with CD4 counts less than 350 cells/µL were defined as having a late HIV diagnosis. Chi-square trend tests were used to compare temporal changes over the years and multivariable logistic regression analyses were used to identify factors associated with late diagnosis.

Results: A total of 2441, 2677, 2591 and 2610 participants were enrolled in 2011, 2012, 2013 and 2014, respectively. Testing for HIV in the last 12 months decreased over the time period, from 59.9% to 52.5% (p<0.001). Late HIV diagnosis remained high and steady, ranging from 33.3% to 44.2% over the years with no significant change over time (p = 0.418). MSM who were older than 24 years (aOR =1.748, p = 0.020 for 25-39 years old; aOR = 3.148, p<0.001 for 40 years old or older), were recruited via internet (aOR = 1.596, p = 0.024), and did not have an HIV test in the past 12 months (aOR = 3.385, p<0.001) were more likely to be late diagnosed.

Conclusions: Our study showed a plateau in HIV testing among MSM in China, in parallel to high levels of late diagnosis. Emerging and innovative strategies such as HIV self-testing and reaching more MSM by internet, both highly acceptable to MSM in China, may reduce late diagnosis.

Abstract  Full-text [free] access 

Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda.

Seremba E, Ssempijja V, Kalibbala S, Gray RH, Wawer MJ, Nalugoda F, Casper C, Phipps W, Ocama P, Serwadda D, Thomas DL, Reynolds SJ. 123. AIDS. 2017 Mar 27;31(6):781-786. doi: 10.1097/QAD.0000000000001399.

Objective: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda.

Methods: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs).

Results: Thirty-nine HBV infections occurred over 3342 person-years, incidence1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P < 0.001], and with lamivudine (3TC) use: (0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI0.1-0.7, P =  < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P < 0.001); and with age: 15-29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3).

Conclusion: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.

Abstract access 

Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda.

Ramachandran A(1), Manabe Y(1,)(2), Rajasingham R(3), Shah M(4).141. BMC Infect Dis. 2017 Mar 23;17(1):225. doi: 10.1186/s12879-017-2325-9.

Background: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost-effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening.

Methods: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients withCD4 < 100 cells/µL. Primary outcomes were expected costs, DALYs, and incremental cost-effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis.

Results: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost-effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651 454 for 100%implementation of screening nationally, while averting 1228 deaths compared to no screening.

Conclusion: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda.

Abstract  Full-text [free] access

Africa, Asia
China, Nigeria, Uganda
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Anti-malarial effect of HIV protease inhibitors

Effect of antiretroviral therapy on malaria incidence in HIV-infected Ugandan adults.

Kasirye RP, Grosskurth H, Munderi P, Levin J, Anywaine Z, Nunn A, Kamali A, Baisley K. AIDS. 2017 Feb 20;31(4):577-582. doi: 10.1097/QAD.0000000000001344.

Introduction: Using the data of a trial on cotrimoxazole (CTX) cessation, we investigated the effect of different antiretroviral therapy (ART) regimens on the incidence of clinical malaria.

Methods: During the cotrimoxazole cessation trial (ISRCTN44723643), HIV-infected Ugandan adults with CD4 at least 250 cells/µl were randomized to receive either CTX prophylaxis or placebo and were followed for a median of 2.5 years. Blood slides for malaria microscopy were examined at scheduled visits and at unscheduled visits when the participant felt unwell. CD4 cell counts were done 6-monthly. Malaria was defined as fever with a positive blood slide. ART regimens were categorized as nucleoside reverse transcriptase inhibitor (NRTI) only, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or protease inhibitor containing. Malaria incidence was calculated using random effects Poisson regression to account for clustering of events.

Results: Malaria incidence in the three ART regimen groups was 9.9 (3.6-27.4), 9.3 (8.3-10.4), and 3.5 (1.6-7.6) per 100 person-years, respectively. Incidence on protease inhibitors was lower than that on the other regimens with the results just reaching significance (adjusted rate ratio 0.4, 95% confidence interval = 0.2-1.0, comparing with NNRTI regimens). Stratification by CTX/placebo use gave similar results, without evidence of an interaction between the effects of CTX/placebo use and ART regimen. There was no evidence of an interaction between ART regimen and CD4 cell count.

Conclusion: There was some evidence that protease inhibitor-containing ART regimens may be associated with a lower clinical malaria incidence compared with other regimens. This effect was not modified by CTX use or CD4 cell count. The antimalarial properties of protease inhibitors may have clinical and public health importance.

Abstract  Full-text [free] access 

Editor’s notes: HIV protease inhibitors (PIs) have been shown to kill various life cycle stages of the malaria parasite both in vitro and in vivo at therapeutic drug levels.  A randomized controlled trial in children previously illustrated that PI-based antiretroviral therapy (ART) was associated with a lower risk of recurrent malaria compared to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART.

This study is the first to present data illustrating a reduction in clinical malaria incidence in adults on a PI-based regimen. The authors used data from the COSTOP trial, which was originally designed to look at the safety of discontinuing trimethoprim-sulfamethoxazole (TMP-SMX, Septrin) in HIV-positive Ugandan adults with a CD4 cell count ≥250 cells/µL. A limitation is that only 4% of study participants were on a PI-based ART regimen, so numbers are small. In addition, the authors were unable to adjust for potential confounders relating to individual health status. However, this analysis is a useful addition to the evidence base, suggesting that PIs may have antimalarial properties of clinical and public health importance, especially settings with high malaria transmission and moderate to high HIV prevalence.

Comorbidity, HIV Treatment
Africa
Uganda
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Is stool testing the answer to the problem of childhood TB diagnosis?

Stool Xpert® MTB/RIF test for the diagnosis of childhood pulmonary tuberculosis at primary clinics in Zimbabwe.

Chipinduro M, Mateveke K, Makamure B, Ferrand RA, Gomo E. Int J Tuberc Lung Dis. 2017 Feb 1;21(2):161-166. doi: 10.5588/ijtld.16.0357.

Objective: To evaluate the diagnostic performance of Xpert® MTB/RIF on stool samples from children with clinical suspicion of pulmonary tuberculosis (PTB) at primary care clinics.

Design: A cross-sectional diagnostic evaluation enrolling 5-16 year olds from whom one induced sputum (IS) sample was tested for microbiological TB confirmation. Results of a single stool sample tested using Xpert® were compared against microbiologically confirmed TB, defined as a positive result on sputum microscopy and/or culture and/or IS Xpert®.

Results: Of 222 children enrolled, 218 had complete microbiological results. The median age was 10.6 years (interquartile range 8-13). TB was microbiologically confirmed in 19/218 (8.7%) children. Of these, respectively 5 (26%), 9 (47%) and 15 (79%) were smear-, culture- and IS Xpert®-positive. Stool Xpert® was positive in 13/19 (68%) microbiologically confirmed cases and 4/199 (2%) microbiologically negative cases. Stool Xpert® detected 76.9% (10/13) of human immunodeficiency virus (HIV) infected and 50% (3/6) of non-HIV-infected children with microbiologically confirmed TB (P = 0.241).

Conclusion: Stool Xpert® is a potential alternative screening test for children with suspected TB if sputum is unavailable. Strategies to optimise the diagnostic yield of stool Xpert® assay need further study.

Abstract  Full-text [free] access 

Xpert® MTB/RIF on Stool is Useful for the Rapid Diagnosis of Tuberculosis in Young Children with Severe Pulmonary Disease

Walters E, van der Zalm MM, Palmer M, Bosch C, Demers AM, Draper H, Goussard P, Schaaf HS, Friedrich SO, Whitelaw A, Warren R, Gie RP, Hesseling AC. Pediatr Infect Dis J. 2017 Jan 31. doi: 10.1097/INF.0000000000001563. [Epub ahead of print]

Background: Tuberculosis (TB) continues to result in high morbidity and mortality in children from resource-limited settings. Diagnostic challenges, including resource-intense sputum collection methods and insensitive diagnostic tests, contribute to diagnostic delay and poor outcomes in children. We evaluated the diagnostic utility of stool Xpert® MTB/RIF (Xpert) compared with bacteriologic confirmation (combination of Xpert® and culture of respiratory samples).

Methods: In a hospital-based study in Cape Town, South Africa, we enrolled children younger than 13 years of age with suspected pulmonary TB from April 2012- August 2015. Standard clinical investigations included tuberculin skin test, chest radiograph and HIV testing. Respiratory samples for smear microscopy, Xpert® and liquid culture included gastric aspirates, induced sputum, nasopharyngeal aspirates and expectorated sputum. One stool sample per child was collected and tested using Xpert®.

Results: Of 379 children enrolled (median age, 15.9 months, 13.7% HIV-infected), 73 (19.3%) had bacteriologically confirmed TB. The sensitivity and specificity of stool Xpert® vs. overall bacteriologic confirmation were 31.9% (95% CI 21.84-44.50%) and 99.7% (95% CI 98.2-100%) respectively. 23/51 (45.1%) children with bacteriologically confirmed TB with severe disease were stool Xpert® positive. Cavities on chest radiograph were associated with Xpert® stool positivity regardless of age and other relevant factors (OR 7.05; 95% CI 2.16-22.98; p=0.001).

Conclusions: Stool Xpert® can rapidly confirm TB in children who present with radiologic findings suggestive of severe TB. In resource-limited settings where children frequently present with advanced disease, Xpert® on stool samples could improve access to rapid diagnostic confirmation and appropriate treatment.

Abstract access

Editor’s notes: It has been known for a long time that Mycobacterium tuberculosis can be detected in stool specimens in some people with pulmonary TB disease. This is because sputum is often swallowed and M. tuberculosis bacilli can survive transit through the gastrointestinal tract. With the challenges of detecting TB in children, and the introduction of molecular diagnostic tools, there has been renewed interest in using stool specimens to improve TB diagnosis.

These two studies from southern Africa evaluated the diagnostic yield and accuracy of Xpert® MTB/RIF testing on stool specimens in children with symptoms compatible with intrathoracic TB. The study populations were different. The children in the South African study were younger than in the Zimbabwean study (median age 16 months vs. 10 years). In South Africa, only one in seven children was HIV positive whereas half the children were HIV positive in the Zimbabwean study. The South African study was conducted at hospital level whereas the Zimbabwean study was at primary health care clinics.

Despite these differences, the main findings were similar. Stool Xpert® was positive in six percent in South Africa and eight percent in Zimbabwe. Sensitivity of stool Xpert® compared to a single culture from induced sputum was 50% in South Africa and 67% in Zimbabwe. A single Xpert® test on stool was no better than a single Xpert® test on induced sputum. There was some evidence from both studies that sensitivity was higher in HIV positive children. However, in South Africa, sensitivity compared to any bacteriological confirmation was substantially lower (32%), as the reference standard included Xpert® and culture tests on multiple specimens. Sensitivity compared to the clinical decision to treat for TB was even lower (14%). This may have reflected the fact that all children in the South African study had chest X-rays and there were several children with intrathoracic lymph node disease.

What does this tell us about the role of Xpert® testing on stool for TB diagnosis in children? The evidence does not seem to provide strong support for scaling up stool Xpert® testing within standard diagnostic algorithms. As the South African study demonstrated, many of the children with positive Xpert® on stool were older children with more severe pulmonary disease. These are the children that may be more likely to produce sputum, and are the ones where we would want to make every effort to get respiratory specimens. This is especially the case in HIV-positive children, among whom there may be many possible diagnoses. Added to all this is the fact that processing and testing stool in the laboratory is not simple, meaning it might be difficult to scale up within decentralised laboratory systems.

It is encouraging that research groups are now addressing the challenge of TB diagnosis in children. It would seem that testing stool specimens for now does not really address the fundamental challenge in children, that they usually have paucibacillary disease often with little or no involvement of the lung parenchyma. The search must go on for better diagnostic tests for TB in children. 

Comorbidity, HIV Treatment
Africa
South Africa, Zimbabwe
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High MDR-TB treatment success rates among people on ART

High treatment success rates among HIV-infected multidrug-resistant tuberculosis patients after expansion of antiretroviral therapy in Botswana, 2006-2013.

Shin SS, Modongo C, Boyd R, Caiphus C, Kuate L, Kgwaadira B, Zetola NM. J Acquir Immune Defic Syndr. 2017 Jan 1;74(1):65-71.

Background: Few studies have examined multidrug-resistant (MDR) tuberculosis (TB) treatment outcomes among HIV-infected persons after widespread expansion of antiretroviral therapy (ART). We describe MDR-TB treatment outcomes among HIV-infected and HIV-uninfected patients in Botswana after ART expansion.

Methods: We retrospectively reviewed data from patients who started MDR-TB therapy in Botswana during 2006-2013. Multivariable regression models were used to compare treatment outcomes between HIV-infected and HIV-uninfected patients.

Results: We included 588 MDR-TB patients in the analysis, of whom, 47 (8.0%) and 9 (1.5%) were diagnosed with pre-extensively drug-resistant (XDR)-TB and XDR-TB, respectively. Of the 408 (69.4%) HIV-infected patients, 352 (86.0%) were on ART or started ART during treatment, and median baseline CD4 T-cell count was 234 cells/mm3. Treatment success rates were 79.4% and 73.0% among HIV-uninfected and HIV-infected patients, respectively (P = 0.121). HIV-infected patients with CD4 T-cell count <100 cells/mm3 were more likely to die during treatment compared with HIV-uninfected patients (adjusted risk ratio = 1.890; 95% CI: 1.098 to 3.254).

Conclusions: High rates of treatment success were achieved with programmatic management of MDR-TB and HIV in Botswana after widespread expansion of ART. However, a 2-fold increase in mortality was observed among HIV-infected persons with baseline CD4 <100 cells/mm3 compared with HIV-uninfected persons.

Abstract access  

Editor’s notes: This article describes the treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) among HIV-positive and HIV-negative people in Botswana between 2006 and 2013, after expansion of the antiretroviral therapy (ART) programme. The investigators used programmatic data for their analysis, and the results therefore reflect “real-life” experience of people in the MDR-TB programme.

The authors found very high rates of treatment success. Some 75% of people started on MDR-TB treatment achieved treatment success, and among people living with HIV the success rate was 73%. This is significantly higher than the 57% treatment success reported in a recent systematic review of HIV-positive MDR-TB people. Pre-treatment counselling, strict directly observed therapy, food and transport incentives, follow-up of people who missed their monthly consultations are all aspects of the MDR-TB (and ART programme) that may have contributed to these high success rates. On the other hand, the inclusion of studies done before widespread access to ART may have contributed to the lower success rates reported in the systematic review. 

The reported treatment success of 79% among HIV-negative people was lower than the 84-89% treatment success reported for the new nine-month MDR-TB regimen endorsed by WHO. However, the authors emphasize that additional research is necessary to evaluate the effectiveness of the nine-month regimen in a similar setting as Botswana, where the majority of MDR-TB people are HIV-positive.

In this study, about 70% of MDR-TB people were HIV-positive, and 20% of people had a CD4 count of less than 100 cells/mm3 at the time of MDR-TB treatment initiation. People with a CD4 less than 100 cells/mm3 were almost twice as likely to die during their MDR-TB treatment compared to HIV-negative people. People living with HIV, with CD4<100 cells/mm3 often have co-morbidities, and are at high risk of dying of diseases other than TB, including cryptococcal meningitis and other opportunistic infections. The authors suggest that additional research is necessary to improve the clinical management of MDR-TB people with advanced immunosuppression.

The authors conclude that to reduce mortality from MDR-TB and other causes, increased efforts are necessary to reach all people living with HIV with ART as part of comprehensive HV care. In June 2016, Botswana launched the “Test and Treat” programme, to provide ART to all people living with HIV, which should contribute to this goal. 

Africa
Botswana
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Person-to-person spread driving XDR-TB epidemic in KwaZulu-Natal

Transmission of extensively drug-resistant tuberculosis in South Africa.

Shah NS, Auld SC, Brust JC, Mathema B, Ismail N, Moodley P, Mlisana K, Allana S, Campbell A, Mthiyane T, Morris N, Mpangase P, van der Meulen H, Omar SV, Brown TS, Narechania A, Shaskina E, Kapwata T, Kreiswirth B, Gandhi NR. N Engl J Med. 2017 Jan 19;376(3):243-253. doi: 10.1056/NEJMoa1604544.

Background: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions.

Methods: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission.

Results: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).

Conclusions: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission.

Abstract   Full-text [free] access

Editor’s notes: This paper provides further evidence to support person-to-person transmission being the main driver of the XDR-TB epidemic in KwaZulu-Natal, the most populous province of South Africa. The study combined classical and molecular epidemiology: detailed characterisation of people’s clinical history and social networks alongside genotypic methods to characterise their TB strains. With the most conservative estimate, almost seven in ten XDR-TB cases resulted from transmission. However, combining the clinical and genotypic information, as many as nine in ten cases may have been attributable to transmission.

So where was transmission happening? This unfortunately was more difficult to answer. Although epidemiological links (mainly at home or at hospitals) could be defined for around one in three cases, many did not share the same TB strain. More detailed understanding of transmission may have been affected by the relatively low coverage of XDR-TB cases by this study. Full information was available for just over one in three laboratory-confirmed XDR-TB cases in the province over the study period. Also, although there was some genetic diversity in the TB strains, there was one dominant strain (LAM4/KZN). This is the strain responsible for the well-characterised clonal outbreak of XDR-TB involving Tugela Ferry.

Most people with XDR-TB in this study were HIV positive. Interestingly, three-quarters of people living with HIV were on ART at the time of their XDR-TB diagnosis, and two-thirds of people had undetectable viral load. This flags up two things. Firstly, it is a reminder that ART alone is unlikely to control the TB (or drug-resistant TB) epidemic in South Africa. Secondly, it raises further questions that could not be definitively answered here as to whether some of these people might have been infected with XDR-TB while accessing HIV treatment and care in the public health system. 

So what do we do with this new information? These findings should encourage us to focus on developing strategies to interrupt drug-resistant TB transmission. We need better evidence of what works in community settings and health care settings. We need better evidence of how to deliver proven programmes. We still do not know whether we might need different activities to interrupt MDR- and XDR-TB transmission, or whether this should just be encompassed within broader strategies to interrupt all TB transmission. South Africa is leading the way in implementing molecular diagnostics to help with earlier detection of drug-resistant TB, and is at the forefront of developing and testing new drug regimens for drug-resistant TB. This provides a solid platform on which to develop public health programmes to stop the spread of drug-resistant TB.

Comorbidity, Epidemiology
Africa
South Africa
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Xpert® for active TB case finding in high prevalence communities

Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial.

Calligaro GL, Zijenah LS, Peter JG, Theron G, Buser V, McNerney R, Bara W, Bandason T, Govender U, Tomasicchio M, Smith L, Mayosi BM, Dheda K. Lancet Infect Dis. 2017 Jan 4. pii: S1473-3099(16)30384-X. doi: 10.1016/S1473-3099(16)30384-X. [Epub ahead of print]

Background: Inadequate case detection results in high levels of undiagnosed tuberculosis in sub-Saharan Africa. Data for the effect of new diagnostic tools when used for community-based intensified case finding are not available, so we investigated whether the use of sputum Xpert®-MTB/RIF and the Determine™ TB LAM urine test in two African communities could be effective.

Methods: In a pragmatic, randomised, parallel-group trial with individual randomisation stratified by country, we compared sputum Xpert®-MTB/RIF, and if HIV-infected, the Determine™ TB LAM urine test (novel diagnostic group), with laboratory-based sputum smear microscopy (routine diagnostic group) for intensified case finding in communities with high tuberculosis and HIV prevalence in Cape Town, South Africa, and Harare, Zimbabwe. Participants were randomly assigned (1:1) to these groups with computer-generated allocation lists, using culture as the reference standard. In Cape Town, participants were randomised and tested at an Xpert®-equipped mobile van, while in Harare, participants were driven to a local clinic where the same diagnostic tests were done. The primary endpoint was the proportion of culture-positive tuberculosis cases initiating tuberculosis treatment in each study group at 60 days. This trial is registered at ClinicalTrials.gov, number NCT01990274.

Findings: Between Oct 18, 2013, and March 31, 2015, 2261 individuals were screened and 875 (39%) of these met the criteria for diagnostic testing. 439 participants were randomly assigned to the novel group and 436 to the routine group. 74 (9%) of 875 participants had confirmed tuberculosis. If late culture-based treatment initiation was excluded, more patients with culture-positive tuberculosis were initiated on treatment in the novel group at 60 days (36 [86%] of 42 in the novel group vs 18 [56%] of 32 in the routine group). Thus the difference in the proportion initiating treatment between groups was 29% (95% CI 9-50, p=0.0047) and 53% more patients initiated therapy in the novel diagnostic group than in the routine diagnostic group. One culture-positive patient was treated based only on a positive LAM test.

Interpretation: Compared with traditional tools, Xpert®-MTB/RIF for community-based intensified case finding in HIV and tuberculosis-endemic settings increased the proportion of patients initiating treatment. By contrast, urine LAM testing was not found to be useful for intensive case finding in this setting.

Abstract access   

Editor’s notes: Undiagnosed tuberculosis (TB) is the main source of ongoing transmission of Mycobacterium tuberculosis in the community.  Community-based intensified TB case finding strategies in high prevalence settings aim to reduce the prevalence of undiagnosed tuberculosis (TB) and thereby to reduce TB transmission. This is the first randomised trial to date comparing a point of contact diagnostic tool, Xpert® MTB/RIF, with a traditional tool, smear microscopy, for community-based intensive case-finding in sub-Saharan Africa.

The key finding was that a community-based intensified strategy using Xpert® MTB/RIF reduced time-to-treatment and increased the proportion of culture-positive people started on treatment in the first 60 days (when culture-based treatment initiation was not included).  Additional findings included a reduction in the number of people with TB treated empirically and a 50% increase in 60-day detection rate compared with smear microscopy. However, there was no difference by study arm in the proportion of culture-positive people who were retained on TB treatment at six months, and this was suboptimal (69% versus 71% for routine versus novel). The study also demonstrated that it was feasible to undertake community-based screening by minimally trained health-care workers using Xpert® in a mobile van with a generator or on site within a community-based clinic. 

It is interesting to note that there were major differences between study sites. In multivariable analysis, study site was the strongest risk factor for a shorter time-to-treatment initiation among culture-positive cases (Harare versus Cape Town - adjusted hazard ratio 7.18, 95% confidence interval 3.69 – 13.96) with screening method (novel versus routine diagnostics) found to have an adjusted hazard ratio of 2.32 (95% confidence interval 1.35 – 3.97). This finding likely reflects differences in the clinical management of Xpert®-negative and smear-negative people with presumed TB between study sites. In Harare, almost all people with a negative test result (in either arm) were referred for chest radiography, and probably because of this, a much larger proportion of study participants were started on anti-tuberculosis treatment in Harare compared to Cape Town (49% versus 9%). There was also a major difference in retention on treatment at six months among culture-positive people (81% in Harare versus 59% in Cape Town). These results highlight the importance of context, including heterogeneity in patient characteristics and differences in quality of health-care, access and practices between settings, in interpreting study findings associated with TB case-finding strategies.

Whether implementation of community-based intensive case finding using Xpert® in high-prevalence areas actually translates into reduced community TB transmission or improved clinical outcomes remains to be determined. 

Africa
South Africa, Zimbabwe
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Anal high-risk HPV and high-grade lesions: screening is required for women living with HIV

Prevalence of anal HPV and anal dysplasia in HIV-infected women from Johannesburg, South Africa.

Goeieman BJ, Firnhaber CS, Jong E, Michelow P, Swarts A, Williamson AL, Allan B, Smith JS, Kegorilwe P, Wilkin TJ. J Acquir Immune Defic Syndr. 2017 Jan 30. doi: 10.1097/QAI.0000000000001300. [Epub ahead of print]

Background: Anal cancer is a relatively common cancer among HIV-infected populations. There are limited data on the prevalence of anal high-risk human papillomavirus (HR-HPV) infection and anal dysplasia in HIV-infected women from resource-constrained settings.

Methods: A cross-sectional study of HIV-infected women age 25-65 recruited from an HIV clinic in Johannesburg, South Africa. Cervical and anal swabs were taken for conventional cytology and HR-HPV testing. Women with abnormal anal cytology and 20% of women with negative cytology were seen for high resolution anoscopy (HRA) with biopsy of visible lesions.

Results: Two hundred women were enrolled. Anal HR-HPV was found in 43%. The anal cytology results were negative in 51 (26%); 97 (49%) had low-grade squamous intraepithelial lesions (SIL), 32 (16%) had atypical squamous cells of unknown significance and 19 (9.5%) had high-grade SIL or atypical squamous cells suggestive of high-grade SIL. On HRA, 71 (36%) had atypia or low-grade SIL on anal histology and 17 (8.5%) had high-grade SIL. Overall 31 (17.5%) had high-grade SIL present on anal cytology or histology. Abnormal cervical cytology was found in 70% and cervical HR-HPV in 41%.

Conclusion: We found a significant burden of anal HR-HPV infection, abnormal anal cytology and high-grade SIL in our cohort. This is the first study of the prevalence of anal dysplasia in HIV-infected women from sub-Saharan Africa. Additional studies are needed to define the epidemiology of these conditions, as well as the incidence of anal cancer, in this population.

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Editor’s notes: Women living with HIV have a higher incidence of anogenital cancers compared to HIV-negative women, even in the ART era. Previous studies have illustrated that women living with HIV in South Africa have a high risk of cervical high-risk (HR)-HPV, and high rates of high-grade cervical intraepithelial neoplasia. This is the first study to report the prevalence of anal HR-HPV and anal high-grade squamous intraepithelial lesions (HSIL+) among women living with HIV in Africa.

This cross-sectional study among 200 women living with HIV attending a HIV treatment centre in Johannesburg, South Africa, the majority (97%) of whom were on ART, reported a high  prevalence of anal HR-HPV and anal HSIL+ by high-resolution anoscopy (43% and 8.5%, respectively). Women with low current CD4+ cell count and with shorter duration of ART use had marginally higher prevalence of anal HR-HPV and HSIL+.

It remains unclear whether high-grade anal lesions among women living with HIV have the same propensity to progress to anal cancer as is known to occur for high-grade cervical lesions to cervical cancer. Studies among HIV-positive and HIV-negative men report frequent spontaneous regression of anal intraepithelial lesions (AIN) and high rates of recurrence following treatment, but longitudinal data are limited among women living with HIV. Prolonged ART use may have contributed to a reduction in HPV-associated cervical lesions, and the same could be true for anal lesions. Larger prospective studies are necessary to define the rates of high-grade lesion incidence and progression and associated risk factors among women living with HIV in order to guide screening and management decisions.  

Comorbidity, Epidemiology
Africa
South Africa
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ART has dramatically improved life expectancy for people living with HIV in KwaZulu-Natal, South Africa

Trends in the burden of HIV mortality after roll-out of antiretroviral therapy in KwaZulu-Natal, South Africa: an observational community cohort study.

Reniers G, Blom S, Calvert C, Martin-Onraet A, Herbst AJ, Eaton JW, Bor J, Slaymaker E, Li ZR, Clark SJ, Barnighausen T, Zaba B, Hosegood V Lancet HIV. 2016 Dec 9. pii: S2352-3018(16)30225-9. doi: 10.1016/S2352-3018(16)30225-9

Background: Antiretroviral therapy (ART) substantially decreases morbidity and mortality in people living with HIV. In this study, we describe population-level trends in the adult life expectancy and trends in the residual burden of HIV mortality after the roll-out of a public sector ART programme in KwaZulu-Natal, South Africa, one of the populations with the most severe HIV epidemics in the world.

Methods: Data come from the Africa Centre Demographic Information System (ACDIS), an observational community cohort study in the uMkhanyakude district in northern KwaZulu-Natal, South Africa. We used non-parametric survival analysis methods to estimate gains in the population-wide life expectancy at age 15 years since the introduction of ART, and the shortfall of the population-wide adult life expectancy compared with that of the HIV-negative population (ie, the life expectancy deficit). Life expectancy gains and deficits were further disaggregated by age and cause of death with demographic decomposition methods.

Findings: Covering the calendar years 2001 through to 2014, we obtained information on 93 903 adults who jointly contribute 535 428 person-years of observation to the analyses and 9992 deaths. Since the roll-out of ART in 2004, adult life expectancy increased by 15.2 years for men (95% CI 12.4-17.8) and 17.2 years for women (14.5-20.2). Reductions in pulmonary tuberculosis and HIV-related mortality account for 79.7% of the total life expectancy gains in men (8.4 adult life-years), and 90.7% in women (12.8 adult life-years). For men, 9.5% is the result of a decline in external injuries. By 2014, the life expectancy deficit had decreased to 1.2 years for men (-2.9 to 5.8) and to 5.3 years for women (2.6-7.8). In 2011-14, pulmonary tuberculosis and HIV were responsible for 84.9% of the life expectancy deficit in men and 80.8% in women.

Interpretation: The burden of HIV on adult mortality in this population is rapidly shrinking, but remains large for women, despite their better engagement with HIV-care services. Gains in adult life-years lived as well as the present life expectancy deficit are almost exclusively due to differences in mortality attributed to HIV and pulmonary tuberculosis.

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Editor’s notes: Health and demographic surveillance system (HDSS) sites allow for monitoring of population health through the collection of detailed data on tens of thousands of individuals. Such sites in countries with high HIV prevalence have played an important role in measuring the effects of large-scale programmes, such as the global roll-out of antiretroviral therapy (ART). The data presented in this paper, from the Africa Centre Demographic Information System (ACDIS) in KwaZulu-Natal, South Africa, span 13 years (2001–14) and represent over 93 000 individuals living in an area with extremely high HIV prevalence (29% in adults aged 15–49 years in 2011). At least 15 000 of people studied were HIV-positive, of whom at least 2000 died. ART was first made available to people living with HIV (PLHIV) in this area in 2004.

Among adults aged 15–49 years, the authors report an overall reduction in death rate from 2001–14.  This translates into large increases in life expectancy (i.e., the expected number of years lived from age 15) of 15 and 17 years for men and women, respectively, between 2001 and 2014.  The changes in life expectancy are greater in people who were confirmed HIV-positive: 18 and 21 years for men and women, respectively, from 2007–14.  The large difference in life expectancies between the sexes that still exists (31 versus 44 years in HIV-positive men and women, respectively) are consistent with previously published estimates from Rwanda and Uganda. This study, however, illustrates that HIV-positive men are catching up to their HIV-negative counterparts faster than women are. The ‘deficit’ in 2014 - the gap in life expectancies between HIV-positive and HIV-negative individuals, was 1.2 years in men but still 5.3 years in women.

The authors propose that increased access to ART is the primary driver of the gains in life expectancy seen in this cohort. To further support this, they include data from verbal autopsies (VAs), which suggest that reductions in deaths due to HIV and pulmonary tuberculosis were responsible for 80% and 90% of the increases in life expectancy in men and women, respectively. VAs have limitations, however, particularly in areas of high HIV prevalence, but the overall mortality patterns suggested by these findings are likely to be accurate, even if the precise estimates differ.

The dramatic increases in life expectancy, in only seven years, for HIV-positive individuals in this cohort add to the encouraging observations from other low- and middle-income countries that many people receiving ART can expect to live for nearly as long as HIV-negative individuals.  Of course, people with advanced disease starting ART are still at high risk of death and there remain considerable challenges in getting treatment to all people in need of it. 

Africa
South Africa
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Adolescents’ concerns: psychosocial needs of young people living with HIV in Thailand

Psychosocial needs of perinatally HIV-infected youths in Thailand: lessons learnt from instructive counseling.

Manaboriboon B, Lolekha R, Chokephaibulkit K, Leowsrisook P, Naiwatanakul T, Tarugsa J, Durier Y, Aunjit N, Punpanich Vandepitte W, Boon-Yasidhi V. AIDS Care. 2016 Dec;28(12):1615-1622. Epub 2016 Jun 26.

Identifying psychosocial needs of perinatally HIV-infected (pHIV) youth is a key step in ensuring good mental health care. We report psychosocial needs of pHIV youth identified using the "Youth Counseling Needs Survey" (YCS) and during individual counseling (IC) sessions. pHIV youth receiving care at two tertiary-care hospitals in Bangkok or at an orphanage in Lopburi province were invited to participate IC sessions. The youths' psychosocial needs were assessed using instructive IC sessions in four main areas: general health, reproductive health, mood, and psychosocial concerns. Prior to the IC session youth were asked to complete the YCS in which their concerns in the four areas were investigated. Issues identified from the YCS and the IC sessions were compared. During October 2010-July 2011, 150 (68.2%) of 220 eligible youths participated in the IC sessions and completed the YCS. Median age was 14 (range 11-18) years and 92 (61.3%) were female. Mean duration of the IC sessions was 36.5 minutes. One-hundred and thirty (86.7%) youths reported having at least one psychosocial problem discovered by either the IC session or the YCS. The most common problems identified during the IC session were poor health attitude and self-care (48.0%), lack of life skills (44.0%), lack of communication skills (40.0%), poor antiretroviral (ARV) adherence (38.7%), and low self-value (34.7%). The most common problems identified by the YCS were lack of communication skills (21.3%), poor health attitude and self-care (14.0%), and poor ARV adherence (12.7%). Youth were less likely to report psychosocial problems in the YCS than in the IC session. Common psychosocial needs among HIV-infected youth were issues about life skills, communication skills, knowledge on self-care, ARV adherence, and self-value. YCS can identify pHIV youths' psychosocial needs but might underestimate issues. Regular IC sessions are useful to detect problems and provide opportunities for counseling.

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Editor’s notes: The study reports on the psychological needs of young people who acquired HIV in the perinatal period.  The needs were highlighted during counselling sessions and in a survey conducted as part of the Happy-Teen Programme in Thailand. Young people (age 11-18) who have perinatally acquired HIV were recruited in two hospitals and from a service run by an orphanage linked to one of the hospitals. Young people took part in two individual ‘instructive counselling’ sessions, and two survey sessions for a needs-assessment questionnaire. Participants reported higher levels of needs in the counselling sessions compared to the questionnaire. Key areas of need identified included: health attitudes and self-care (e.g., diet, sleep, drug use); issues with sexual risk and difficulties communicating with sexual partners; HIV treatment adherence problems; concerns about HIV-associated stigma; and concerns about peer pressure. The study illustrates the difference in the quality of findings obtained from data collected via the questionnaire in comparison with data collected via sessions with counsellors. The counsellors were people that the young people knew for some time and trusted. The study highlights the importance of counselling with young people to improve self-esteem and health-associated behaviours.  Counsellors are also important to provide referrals for more severe mental health issues. 

Asia
Thailand
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