Articles tagged as "Comorbidity"

How many people have really died of HIV/AIDS in South Africa?

HIV/AIDS in South Africa: how many people died from the disease between 1997 and 2010?

Bradshaw D, Msemburi W, Dorrington R, Pillay-van Wyk V, Laubscher R, Groenewald P, team SN. AIDS. 2015 Oct 27. [Epub ahead of print]

Objectives: Empirical estimates of the number of HIV/AIDS deaths are important for planning, budgeting, and calibrating models. However, there is an extensive misattribution of HIV/AIDS as an underlying cause-of-death. This study estimates the true numbers of AIDS deaths from South African vital statistics between 1997 and 2010.

Methods: Individual-level cause-of-death data were grouped according to a local burden of disease list and source causes (i.e. causes under which AIDS deaths are misclassified) that recorded a rapid increase. After adjusting for completeness of registration, mortality rate of the source causes, by age and sex, was regressed on lagged HIV prevalence to estimate the rate of increase correlated with HIV. Background trends in the source-cause mortality rates were estimated from the trend experienced among 75-84 year olds.

Results: Of 214 causes considered, 19 were identified as potential sources for cause misattribution. High proportions of deaths from tuberculosis, lower respiratory infections (mostly pneumonia), diarrhoeal diseases, and ill-defined natural causes were estimated to be HIV-related, with only 7% of the estimated AIDS deaths being recorded as HIV. Estimated HIV/AIDS deaths increased rapidly, then reversed after 2006, totalling 2.8 million deaths over the whole period. The number was lower than model estimates from UNAIDS and the Global Burden of Disease Study.

Conclusion: Empirically based estimates confirm the considerable loss of life from HIV/AIDS and should be used for calibrating models of the AIDS epidemic which generally appear too low for infants but too high for other ages. Doctors are urged to specify HIV on death notifications to provide reliable cause-of-death statistics.

Abstract access 

Editor’s notesIn many countries, the true number of HIV-associated deaths is significantly under-reported in national vital registration data making it difficult to monitor the epidemic trends from this source. This study describes new estimates of HIV-associated mortality based on empirical vital registration data which aimed to provide accurate estimates of the numbers of HIV-associated deaths in South Africa. The study estimates that, from 1997-2010, 2.86 million deaths in South Africa were due to HIV – over one-third of all deaths. However, relatively few deaths, 7%, were registered as HIV-associated. At the peak of the epidemic in 2006 the vital registration derived estimates show lower trends than other models. All models estimated a decline in the number of HIV-associated deaths post-2008, a finding which is consistent with the extensive roll-out of antiretroviral therapy in South Africa, and with trends reported from verbal autopsy data for all deaths in rural South African demographic surveillance sites. This paper highlights the importance of reporting accurate causes for HIV-associated deaths in the death registration process - however, without de-stigmatisation of HIV, this is going to be difficult to achieve.

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

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

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

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

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

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

Abstract  Full-text [free] access

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

Avoid TB deaths
Basic science, Comorbidity
Africa
South Africa
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Patient-provider encounters are a key factor in ART usage in the United States

Retained in HIV care but not on antiretroviral treatment: a qualitative patient-provider dyadic study.

Christopoulos KA, Olender S, Lopez AM, Lekas HM, Jaiswal J, Mellman W, Geng E, Koester KA. PLoS Med. 2015 Aug 11;12(8):e1001863. doi: 10.1371/journal.pmed.1001863. eCollection 2015.

Background: Patients retained in HIV care but not on antiretroviral therapy (ART) represent an important part of the HIV care cascade in the United States. Even in an era of more tolerable and efficacious ART, decision making in regards to ART offer and uptake remains complex and calls for exploration of both patient and provider perspectives. We sought to understand reasons for lack of ART usage in patients meeting the Health Resources Services Administration definition of retention as well as what motivated HIV primary care appointment attendance in the absence of ART.

Methods and findings: We conducted a qualitative study consisting of 70 in-depth interviews with ART-naive and ART-experienced patients off ART and their primary care providers in two urban safety-net HIV clinics in San Francisco and New York. Twenty patients and their providers were interviewed separately at baseline, and 15 dyads were interviewed again after at least 3 mo and another clinic visit in order to understand any ART use in the interim. We applied dyadic analysis to our data. Nearly all patients were willing to consider ART, and 40% of the sample went on ART, citing education on newer antiretroviral drugs, acceptance of HIV diagnosis, social support, and increased confidence in their ability to adhere as facilitators. However, the strength of the provider recommendation of ART played an important role. Many patients had internalized messages from providers that their health was too good to warrant ART. In addition, providers, while demonstrating patient-centered care through sensitivity to patients experiencing psychosocial instability, frequently muted the offer of ART, at times unintentionally. In the absence of ART, lab monitoring, provider relationships, access to social services, opiate pain medications, and acute symptoms motivated care. The main limitations of this study were that treatment as prevention was not explored in depth and that participants were recruited from academic HIV clinics in the US, making the findings most generalizable to this setting.

Conclusions: Provider communication with regard to ART is a key focus for further exploration and intervention in order to increase ART uptake for those retained in HIV care.

Abstract  Full-text [free] access

Editor’s notes: This paper draws on qualitative data from two clinics in the United States of America.  It examines the barriers to ART uptake in this new era of ART from the perspectives of people who are retained in clinic care and not currently on ART, and their primary care providers. It further explores factors that have promoted peoples’ regular primary care attendance even in the absence of ART. One of the strengths of this paper is the dyadic approach to the data collection which enabled the authors to compare and contrast the narratives of both care users and providers. The findings of this paper are useful as we reflect on the 90-90-90, an ambitious treatment target recently adopted by UNAIDS to help end the AIDS epidemic.

Recent studies including HPTN 052 and the Strategic Timing of AntirRetroviral Treatment (START) studies have highlighted the individual and public health benefits of early initiation of antiretroviral therapy (ART), regardless of CD4 count. The 90-90-90 target is that by 2020, 90% of all people living with HIV will know their status, 90% of people diagnosed with HIV infection will receive sustained antiretroviral therapy and 90% of people receiving antiretroviral therapy, will have viral suppression.

The findings of this article offer important challenges to sub-Saharan Africa and other resource-poor settings for meeting the 90-90-90 target.  First, although the DART trial illustrated that first-line ART can be delivered safely without routine tests, in this study, many people remained engaged in care because of laboratory monitoring of their health status. Second, many of the people valued strong connections to their healthcare providers which were developed through patient-centred medical care.  This contrasts with treatment contexts such as those in sub-Saharan Africa where people may be less likely to see the same provider continuously or even at consecutive visits. Third, access to additional social and acute care services also motivated some participants to maintain primary care visit attendance. In resource poor contexts, such services are rarely available. Understanding how to retain people on ART in resource-poor settings where economic, social and contextual factors differ, will be an important objective for both individual and public health approaches to managing the epidemic.

Northern America
United States of America
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Understanding delays in TB diagnosis: where do people go before accessing TB services?

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

Cancer incidence following expansion of HIV treatment in Botswana

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

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

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

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

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

Abstract  Full-text [free] access


 

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

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

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

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

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

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

Abstract access 

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

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

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

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

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

Avoid TB deaths
Africa
Botswana, Uganda
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High TB incidence in children in Mozambique

Incidence of tuberculosis among young children in rural Mozambique.

López-Varela E, Augusto OJ, Gondo K, Garcia-Basteiro AL, Fraile O, Ira T, Ribo Aristizabal JL, Bulo H, Munoz Gutierrez J, Aponte J, Macete E, Sacarlal J, Alonso PL. Pediatr Infect Dis J. 2015 Jul;34(7):686-92. doi: 10.1097/INF.0000000000000710.

Background: Tuberculosis (TB) contributes significantly to child morbidity and mortality. This study aimed to estimate the minimum community-based incidence rate of TB among children <3 years of age in Southern Mozambique.

Methods: Between October 2011 and October 2012, in the Manhica District Health and Demographic Surveillance System, we enrolled prospectively all presumptive TB cases younger than 3 years of age through passive and active case finding. Participants included all children who were either symptomatic or were close contacts of a notified adult smear-positive pulmonary TB. Children were clinically evaluated at baseline and follow-up visits. Investigation for TB disease included chest radiography, HIV and tuberculin skin testing as well as gastric aspirate and induced sputum sampling, which were processed for smear, culture and mycobacterial molecular identification.

Results: During the study period, 13 764 children <3 years contributed to a total of 9575 person-years. Out of the 789 presumptive TB cases enrolled, 13 had TB culture confirmation and 32 were probable TB cases. The minimum community-based incidence rate of TB (confirmed plus probable cases) was 470 of 100 000 person-years (95% confidence interval: 343-629 of 100 000). HIV co-infection was present in 44% of the TB cases.

Conclusion: These data highlight the huge burden of pediatric TB. This study provides one of the first prospective population-based incidence data of childhood tuberculosis and adds valuable information to the global effort of producing better estimates, a critical step to inform public health policy.

Abstract access 

Editor’s notes: Mozambique is one of the few high HIV/TB burden countries where TB prevalence and incidence has not improved in recent years. This prospective cohort study nested within a rural demographic surveillance site brings to light the immense burden of paediatric tuberculosis in the southern part of the country. The findings of an estimated minimum community-based TB incidence rate in children aged < 3 years of 470 per 100 000 person years (nearly double the number of cases notified) emphasise the gross under-detection of paediatric tuberculosis in this region. 

Children are unlikely to contribute to onward transmission of Mycobacterium tuberculosis (Mtb) because they rarely have large numbers of bacilli in respiratory secretions. Thus, from a public health point of view, childhood tuberculosis has not until recently been considered a priority in high burden settings. One of the study’s strengths is the huge effort made to confirm TB diagnoses, which, due to low numbers of bacilli in sputum and inability to produce sputum samples, is notoriously difficult in young children.  Accurate estimates of paediatric TB (especially in the very young, e.g. ≤3 years), as attempted by this population-based study, act as a critical indicator of the effectiveness of programmes to curtail community transmission. These findings therefore signal an extremely high level of on-going Mtb transmission and the urgent need for effective public health programmes to halt the TB/HIV epidemic in Mozambique.

Avoid TB deaths
Comorbidity
Africa
Mozambique
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Tenofovir-based regimens improve outcomes in HIV-HBV co-infection

Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks.

Thio CL, Smeaton L, Hollabaugh K, Saulynas M, Hwang H, Saravanan S, Kulkarni S, Hakim J, Nyirenda M, Iqbal HS, Lalloo UG, Campbell TB, Lockman S, Currier JS. AIDS. 2015 Jun 19;29(10):1173-82. doi: 10.1097/QAD.0000000000000686.

Objectives: To explore factors associated with short and long-term hepatitis B virus (HBV) DNA suppression in a multinational cohort of HIV-HBV co-infected patients receiving HBV-active antiretrovirals.

Methods: One hundred and fifteen HIV-HBV co-infected patients participating in one of the two global randomized clinical trials conducted by the Adult AIDS Clinical Trials Group of different antiretroviral regimens received either HBV monotherapy with either lamivudine or emtricitabine (N = 56), or HBV dual therapy with tenofovir disoproxil fumarate (TDF) + lamivudine or emtricitabine (N = 59). Associations of pretreatment characteristics with the primary (HBV DNA <200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound.

Results: The proportion with HBV DNA below 200 IU/ml was 60% (95% confidence interval 50-69%) at 24 weeks and 79% (95% confidence interval 69-88%) at 144 weeks. Pretreatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and aspartate aminotransferase, but only pretreatment HBV DNA remained associated with long-term suppression (P < 0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual-therapy group achieved HBV DNA below 200 IU/ml (P = 0.007). A higher proportion of hepatitis B e antigen-negative patients (n = 57) achieved HBV DNA below 200 IU/ml at any point, regardless of the therapy group. All 12 patients with emergence of lamivudine-resistant mutants were in the monotherapy group.

Conclusions: TDF-based dual HBV-active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings in which TDF may not be universally available, lamivudine or emtricitabine HBV monotherapy is a reasonable option in patients with low HBV replication.

Abstract access 

Editor’s notes: Hepatitis B virus infection remains a leading cause of preventable morbidity and mortality globally, through cirrhosis and liver cancer. In settings with a high prevalence of HIV-HBV coinfection, there is an opportunity to optimise clinical management within the public health approach to antiretroviral therapy. This study adds to the evidence base suggesting that antiretroviral regimens containing lamivudine/emtricitabine and tenofovir are associated with better virologic outcomes than regimens without tenofovir for people co-infected with HIV and HBV. In this study, a post hoc analysis of two multicentre randomised controlled trials, regimens with two HBV-active agents provided more durable virologic suppression and limited the emergence of lamivudine-resistant HBV strains. Although recommendations about the treatment of HIV-HBV coinfection are incorporated into WHO antiretroviral guidelines, testing for HBV infection within antiretroviral programmes is still uncommon and tenofovir is not universally employed in standard first-line antiretroviral regimens. With an increasing number of people switching to second-line antiretroviral regimens, there is the additional challenge of identifying HBV infection in order to maintain HBV-active agents within the second-line regimen. There is now a need for better evidence around how to operationalise these recommendations within national antiretroviral programmes.        

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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Diminished immunity despite MMR immunisation in children with perinatally-acquired HIV

Immunity to measles, mumps and rubella in US children with perinatal HIV infection or perinatal HIV exposure without infection.

Siberry GK, Patel K, Bellini W, Karalius B, Purswani M, Burchett SK, Meyer WA, 3rd, Sowers SB, Ellis A, Van Dyke RB, Pediatric HIVACS, Pediatric  HIV AIDS Cohort Study PHACS. Clin Infect Dis. 2015 Jun 9. pii: civ440. [Epub ahead of print]

Background: Children with perinatal HIV infection (PHIV) may not be protected against measles, mumps and rubella because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort.

Methods: PHIV and HEU were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007-2009. At annual visits, demographic, laboratory, immunization and clinical data were abstracted and serologic specimens were collected. Most recent serologic specimen was used to determine measles seroprotection by plaque-reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained cART was defined as taking cART for at least 3 months.

Results: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57%[95% CI: 52-62%] vs. 99% [95% CI: 96-100%]), rubella seroprotection (65% [95% CI: 60-70%] vs. 98% [95% CI: 95-100%]), and mumps seropositivity (59% [95% CI: 55-64%] vs. 97% [95% CI: 94-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar.

Conclusions: High proportions of PHIV children, but not HEU children, lack serologic evidence of immunity to measles, mumps and rubella, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity.

Abstract access 

Editor’s notes: Administration of combination measles, mumps and rubella (MMR) vaccine has resulted in dramatic declines in these diseases. Children with HIV, however, may be susceptible to vaccine-preventable diseases despite immunisation, due to weaker or short-lived immunological responses following immunisation. Children living with HIV may be at higher risk of more severe disease. In addition, children who are susceptible to these diseases may contribute to community risk of outbreaks as control of measles, mumps and rubella depends upon a high proportion of the population being immune.

This study demonstrates that sero-protection to rubella and measles and sero-positivity to mumps was substantially lower among children with HIV aged seven to 15 years than among HIV-exposed but HIV-negative children. Notably, nearly all children with HIV in this study had received the full two-dose series of MMR vaccines, in contrast to previous studies where HIV infection has been a risk factor for failure to receive recommended immunisations. Also, despite concerns that HIV-exposed, but HIV-negative children may have subtle immunological abnormalities that could impair their responses to vaccines, the rates of sero-protection and sero-immunity in this group were high, and comparable to rates in the general population.

Previous studies have illustrated that immunosuppression, lack of antiretroviral therapy (ART) or incomplete HIV virologic suppression are associated with a poor response to vaccines. This study demonstrates that a high proportion of older children and youth (all infected perinatally) may not be protected against MMR despite achieving virologic suppression and good immune status with ART.  Timing of receipt of MMR immunisation in relation to ART, but not overall number of vaccine doses, was independently associated with seropositivity to MMR vaccine. Children who received MMR doses after being on sustained ART had significantly higher levels of sero-positivity and sero-protection than children who received MMR vaccine before ART was instituted.    

This study has important policy implications. ART coverage in children globally is still less than coverage in adults. Many children with HIV start ART only in older childhood. Early ART for children followed by the standard MMR schedule as well as repeating MMR vaccine dosing for older children, particularly children who received MMR vaccine prior to starting ART, will be important to avert the risk of these vaccine-preventable infections in this vulnerable population.     

Avoid TB deaths
Northern America
United States of America
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Xpert testing - rationalise with chest X-ray or HIV pre-screening?

Implementation research to inform the use of Xpert MTB/RIF in primary health care facilities in high TB and HIV settings in resource constrained settings.

Muyoyeta M, Moyo M, Kasese N, Ndhlovu M, Milimo D, Mwanza W, Kapata N, Schaap A, Godfrey Faussett P, Ayles H. PLoS One. 2015 Jun 1;10(6):e0126376. doi: 10.1371/journal.pone.0126376. eCollection 2015.

Background: The current cost of Xpert MTB RIF (Xpert) consumables is such that algorithms are needed to select which patients to prioritise for testing with Xpert.

Objective: To evaluate two algorithms for prioritisation of Xpert in primary health care settings in a high TB and HIV burden setting.

Method: Consecutive, presumptive TB patients with a cough of any duration were offered either Xpert or Fluorescence microscopy (FM) test depending on their CXR score or HIV status. In one facility, sputa from patients with an abnormal CXR were tested with Xpert and those with a normal CXR were tested with FM ("CXR algorithm"). CXR was scored automatically using a Computer Aided Diagnosis (CAD) program. In the other facility, patients who were HIV positive were tested using Xpert and those who were HIV negative were tested with FM ("HIV algorithm").

Results: Of 9482 individuals pre-screened with CXR, Xpert detected TB in 2090/6568 (31.8%) with an abnormal CXR, and FM was AFB positive in 8/2455 (0.3%) with a normal CXR. Of 4444 pre-screened with HIV, Xpert detected TB in 508/2265 (22.4%) HIV positive and FM was AFB positive in 212/1920 (11.0%) in HIV negative individuals. The notification rate of new bacteriologically confirmed TB increased; from 366 to 620/100 000/yr and from 145 to 261/100 000/yr at the CXR and HIV algorithm sites respectively. The median time to starting TB treatment at the CXR site compared to the HIV algorithm site was: 1(IQR 1-3 days) and 3 (2-5 days) (p<0.0001) respectively.

Conclusion: Use of Xpert in a resource-limited setting at primary care level in conjunction with pre-screening tests reduced the number of Xpert tests performed. The routine use of Xpert resulted in additional cases of confirmed TB patients starting treatment. However, there was no increase in absolute numbers of patients starting TB treatment. Same day diagnosis and treatment commencement was achieved for both bacteriologically confirmed and empirically diagnosed patients where Xpert was used in conjunction with CXR.

Abstract  Full-text [free] access

Editor’s notes: Although many countries have begun to deploy molecular TB diagnostics, the cost of these technologies remains prohibitive for widespread use in low- and middle-income countries. This study in Zambian primary health care clinics aimed to explore whether the use of Xpert® MTB/RIF could be rationalised by pre-screening individuals with cough, either by chest X-ray (CXR) or by HIV testing. CXR screening only marginally reduced the use of Xpert® (as three-quarters of people screened had an abnormal CXR, using digital X-ray and computerised interpretation). Restricting use of Xpert® to those known to be HIV-positive reduced the number of Xpert® tests by around half. Under both algorithms, the proportion testing Xpert® positive was very high (22-32%), suggesting that too few people were being identified as needing TB investigation. Similar to other studies of Xpert® implementation, the overall number of people starting TB treatment did not increase with the introduction of Xpert®. However, the proportion of people starting TB treatment who had microbiological confirmation did increase substantially under both algorithms. Empirical TB treatment (meaning initiation of treatment without microbiological confirmation) remained common, in the X-ray algorithm particularly where a third of people with an abnormal CXR but a negative Xpert® were started on TB treatment. This study was not designed to determine how many people who genuinely had TB were missed by each algorithm. Also this paper did not include cost-effectiveness analyses. Based on this evidence, neither of these algorithms can be clearly recommended. Further evaluation of different screening and testing strategies will be important to inform the scale-up of molecular diagnostics.   

Avoid TB deaths
Africa
Zambia
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Early postnatal cytomegalovirus infection may predict subsequent HIV transmission through breastfeeding

Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers.

Chang TS, Wiener J, Dollard SC, Amin MM, Ellington S, Chasela C, Kayira D, Tegha G, Kamwendo D, Jamieson DJ, van der Horst C, Kourtis AP; BAN Study Team. AIDS. 2015 Apr 24;29(7):831-6. doi: 10.1097/QAD.0000000000000617

Background: Cytomegalovirus (CMV) infection can be acquired in utero or postnatally through horizontal transmission and breastfeeding. The effect of postnatal CMV infection on postnatal HIV transmission is unknown.

Methods: The Breastfeeding, Antiretrovirals and Nutrition study, conducted in Malawi, randomized 2369 mothers and their infants to three antiretroviral prophylaxis arms - mother (triple regimen), infant (nevirapine), or neither - for 28 weeks of breastfeeding, followed by weaning. Stored plasma and peripheral blood mononuclear cell specimens were available for 492 infants at 24 weeks and were tested with CMV PCR. Available samples from infants who were CMV PCR-positive at 24 weeks were also tested at birth (N = 242), and from infants PCR-negative at 24 weeks were tested at 48 weeks (N = 96). Cox proportional-hazards models were used to determine if CMV infection was associated with infant morbidity, mortality, or postnatal HIV acquisition.

Results: At 24 weeks of age, CMV DNA was detected in 345/492 infants (70.1%); the estimated congenital CMV infection rate was 2.3%, and the estimated rate of CMV infection at 48 weeks was 78.5%. CMV infection at 24 weeks was associated with subsequent HIV acquisition through breastfeeding or infant death between 24 and 48 weeks of age (hazard ratio 4.27, P = 0.05).

Conclusion: Most breastfed infants of HIV-infected mothers in this resource-limited setting are infected with CMV by 24 weeks of age. Early CMV infection may be a risk factor for subsequent infant HIV infection through breastfeeding, pointing to the need for comprehensive approaches in order to achieve elimination of breastfeeding transmission of HIV.

Abstract access 

Editor’s notes: Studies have illustrated that mother-to-child HIV transmission is more frequent among neonates with congenital cytomegalovirus (CMV) infection. Infants co-infected with HIV and CMV have higher rates of HIV disease progression and death. This study using data and samples of infant plasma and peripheral blood mononuclear cells are from the Breastfeeding, Antiretrovirals and Nutrition (BAN) randomised, controlled clinical trial (RCT). The study examines whether postnatal CMV infection in the infant is associated with HIV transmission through breastfeeding. The study investigates the relationship between postnatal antiretroviral therapy and postnatal CMV acquisition. The data suggests that early postnatal CMV infection in an HIV-exposed uninfected infant may predict subsequent HIV transmission through breastfeeding and infant mortality. The study confirmed previous findings that approximately 70% of breastfed infants born to mothers living with HIV in low-income settings acquire CMV infection by six months of age. However, the study did not find an association between maternal antiretroviral therapy and the risk of postnatal CMV transmission. It is important to note that in the RCT, antiretroviral therapy was only initiated at the onset of labour.  The effect of maternal antiretroviral therapy taken earlier in pregnancy on the prevention or delay of CMV acquisition remains unknown, although a few observational studies have found that maternal antiretroviral therapy reduces congenital and early postnatal CMV infection. It is biologically plausible that antiretroviral therapy reduces or prevents CMV reactivation in the mother, thus preventing transient episodes of maternal CMV viraemia. This mechanism could explain reduced CMV transmission to the infant (be that before or after birth). HIV-exposed but uninfected infants experience higher morbidity and mortality; any such disease attributable to CMV could therefore potentially be reduced by initiation of antiretroviral therapy earlier in pregnancy.

Africa
Malawi
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