There are many successful global health research partnerships, but little information is available about what makes them successful. We asked 14 research colleagues from Uganda, Kenya, and the United States who have extensive global health research experience about what they considered the top three factors that led to or impeded successful international research collaborations. Four key factors were identified: 1) mutual respect and benefit, 2) trust, 3) good communication, and 4) clear partner roles and expectations. Initial and ongoing assessment of these factors in global health research partnerships may prevent misunderstandings and foster a collaborative environment that leads to successful research.
HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed.
Thirty-one children from Malawi aged 4–62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor.
We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03).
LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings.
To investigate the effect of subsequent pregnancies on HIV disease progression among HIV-infected women at Mulago Hospital, Uganda.
In a retrospective cohort study, data were analyzed from women enrolled in the Mother-To-Child Transmission Plus program from March 2003 to December 2011. The CD4 cell count, the development of new AIDS-defining opportunistic infections, and the AIDS-related mortality were compared between women with and without subsequent pregnancies.
Overall, 409 women were enrolled and 195 (47.7%) had subsequent pregnancies. Antiretroviral therapy (ART) was initiated in 143 (73.3%) women with and 155 (72.4%) women without subsequent pregnancies. Kaplan–Meier analysis for women receiving ART showed no differences between women with and without subsequent pregnancies in the median times to clinical failure (62.7 vs 64.7 months; P = 0.31), immunological failure (68.8 vs 75.5 months; P = 0.10), and death (68.8 vs 75.5 months; P = 0.53). In a Cox regression analysis, subsequent pregnancies were not associated with immunological failure during follow-up (adjusted hazard ratio 1.13, 95% confidence interval 0.06–2.09).
Subsequent pregnancies could have no detrimental effect on HIV disease progression among HIV-infected women whose treatment is well managed.
HIV progression; Maternal mortality; Mulago; Subsequent pregnancies; Uganda; Women
Background. Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)–infected children.
Methods. CD4+ T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART.
Results. There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4–11.4 years) and 5.8 years (IQR, 2.3–9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%–9%) and 13% (IQR, 8%–18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4+ T-cell count ratio (calculated as the ratio of the subject's CD4+ T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4+ and CD8+ T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8+ T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died).
Conclusions. While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.
HIV; Africa; children; inflammation; immunosuppression
To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and investigate other predictors of response.
Observational analysis within the ARROW randomised trial.
sdNVP exposure was ascertained by caregiver’s self-report when the child initiated NNRTI based ART. Viral load (VL) was assayed retrospectively over median 4.1 years follow-up. Multivariable logistic regression models were used to identify independent predictors of VL <80 copies/ml 48 and 144 weeks after ART initiation (backwards elimination, exit p=0.1).
Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP exposed children versus 21 (14-27) months in 289 non-exposed children (36% vs 20% <12 months). At week 48, 49/73 (67%) sdNVP exposed and 154/272 (57%) non-exposed children had VL<80 copies/ml (adjusted (a)OR=2.34 [1.26-4.34] p=0.007); 79% and 77% had VL<400copies/ml. Suppression was significantly lower in males (p=0.009), those with higher pre-ART VL (p=0.001), taking syrups (p=0.05) and with lower self-reported adherence (p=0.04). At week 144, 55/73 (75%) exposed and 188/272 (69%) non-exposed had <80 copies/ml (aOR=1.75 [0.93-3.29] p=0.08). There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (p>0.3) or NNRTIs (p>0.1) (n=88) at week 144.
Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination nevirapine-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over one year and even if exposed to sdNVP.
HIV; Africa; children; antiretroviral therapy; viral load; sdNVP
There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis.
Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models.
After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95 % CI, 1.5–2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2–13.4) versus 1.2/100 child-years (0.8–1.6) after 52 weeks). A higher TB risk was independently associated with younger age (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI + 2NRTI.
Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue) = 3.0 (95 % CI, 1.1–8.3), P = 0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001).
TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0593-7) contains supplementary material, which is available to authorized users.
Antiretroviral therapy; HIV; Incident tuberculosis; Pediatric
Recent human studies support historical animal studies that suggested an association between peripheral blood monocyte:lymphocyte(ML) ratio and tuberculosis(TB) disease. To evaluate generalizability of this finding, we modelled the association between peripartum ML ratio and incident TB disease within 18 months postpartum amongst 1202 HIV-infected women in South Africa, Tanzania, Uganda and Zimbabwe. The ML ratio was associated with increased risk of TB disease independently to combination antiretroviral-therapy(cART), WHO stage or CD4 count(HRadjusted = 1.22;95% CI 1.07–1.4;p=0.003 per 0.1 unit increase in ML ratio).
Tuberculosis; HIV; pregnancy; monocytes; lymphocytes; ML ratio
Effective Prevention of Mother to child Transmission of HIV (PMTCT) relies heavily on follow-up of HIV-infected women and infants from antenatal, through postnatal, to the end of the breastfeeding period. In Uganda, postnatal (PNC) follow-up remains below 50 % creating a missed opportunity for linkage to comprehensive HIV care and early infant diagnosis (EID). We evaluated the use of HIV infected peer mothers (peers), community lay persons and Village health team (VHT) members to improve PNC follow up and EID in urban and rural health units.
Study participants were HIV-infected women recruited from antenatal clinics at three urban clinics (Mulago, Rubaga and Mengo hospitals) and one rural health centre (Mpigi Health centre IV) between January and September 2010. The women were followed through delivery and the mother-infant pairs for the 6-week postnatal visit and up to 14 weeks for EID. Peers, community lay persons and VHT members were identified and trained in basic PMTCT and reproductive health (RH). They were then assigned to study clinic to support and follow study participants, their partners and infants through provision of health education, counseling, home visits, and phone call reminders. Six week PNC attendance was measured as a proportion of mother-infant pairs that returned for the 6-week postnatal follow up visit (5–8 weeks) while EID was measured as the proportion of HIV-exposed live birth that had an HIV test done by 14 weeks of age. Data at baseline (one year before the intervention) was compared with that during the one year study period among study participants and HIV infected women and their HIV-exposed infants in the whole clinic population.
A total of 558 HIV-infected pregnant women were recruited for the study, 47 mother-infant pairs were censured before 6 weeks due to stillbirth (14), infant death < 6 weeks (23), death of participant (04) and loss to follow up before delivery (6). 401/511 (78.5 %) of mother-infant pairs returned to the study clinics at six-week, while 441/511 (86.3 %) infants were tested for HIV infection by 14 weeks of age. The baseline six-week PNC follow up was 37.7 % and increased during the study period to 78.5 % and 39.1 % among study participants and whole clinic population respectively, an incremental difference of 39.4 % (P < 0.001). EID increased from a baseline of 53.6 % to 86.3 % and 65.8 % among study and whole clinic population respectively during the study period, an incremental difference of 20.5 % (P < 0.001).
Use of peers, community lay persons and VHT members led to a significant increase in six-week postnatal follow up of HIV infected women and EID among HIV exposed infants in the four study clinics. Our study supports the use of peers to improve early postnatal follow up and EID and should be implemented in other health units to support the PMTCT cascade.
PMTCT; HIV; Postnatal; Peers mothers; Community lay persons; Early Infant Diagnosis
HIV status disclosure is a difficult emotional task for HIV-infected persons and may create the opportunity for both social support and rejection. In this study, we evaluated the proportions, patterns, barriers and outcomes of HIV- 1 status disclosure among a group of women in Uganda.
An exit interview was conducted one year post-partum for 85 HIV-infected women who participated in a study of HIV-1 transmission rates among NVP-experienced compared with NVP-naïve women in “The Nevirapine Repeat Pregnancy (NVP-RP) Study” at the Makerere University-Johns Hopkins University Research Collaboration, Kampala-Uganda, between June 2004 and June 2006.
Of the 85 women interviewed, 99 % had disclosed their HIV status to at least one other person. Disclosure proportions ranged between 1 % to employer(s) and 69 % to a relative other than a parent. Only 38 % of the women had disclosed to their sex partners. Women with an HIV-infected baby were more likely than those with an uninfected baby to disclose to their sex partner, OR 4.9 (95 % CI, 2.0 –11.2), and women were less likely to disclose to a partner if they had previously disclosed to another relative than if they had not, OR 0.19 (95 % CI, 0.14–0.52). The most common reasons for non-disclosure included fear of separation from the partner and subsequent loss of financial support 34 %, and not living with the partner (not having opportunities to disclose) 26 %. While most women (67 %) reported getting social support following disclosure, 22 % reported negative outcomes (neglect, separation from their partners, and loss of financial support). Following disclosure of HIV status, 9 % of women reported that their partner (s) decided to have an HIV test.
Results from this study show high overall HIV disclosure proportions and how this disclosure of HIV status can foster social support. However, proportions of disclosure specifically to male sex partners were low, which suggests the need for interventions aimed at increasing male involvement in perinatal care, along with supportive counseling.
HIV status; Disclosure; Perinatal; Mother-to-child; Partner
The global tuberculosis (TB) estimate in 2011 was 500,000 cases among children under 15 years representing 5.7 % of all cases and 64, 000 deaths among HIV negative children representing 6.5 % of the total deaths. In Uganda, the child TB cases reported in 2012 made up less than 3 % of the total cases while recent modelling estimates it at 15–20 % of adult cases. Mapping of these cases in Kampala district most especially for the children under five years would reflect recent transmission in the various communities in the district. We therefore conducted a retrospective study of reported child TB cases in Kampala district Uganda for 2009–2010 to provide an estimate of child TB incidence and map the cases.
This was a retrospective cross-sectional study on data collected from the health unit TB registers in the five divisions of Kampala district, Uganda. The data was a starting point in preparation for a TB Vaccine study in children. The extracted data spanned a period from 1st January 2009 to 31st December 2010. The projected population of children below 15 years was 637,922 in 2009 and 744,750 in 2010 for Kampala district. We based our projections on the National Bureau of Statistics most recent census report of 2002 before the study duration while assuming a population growth rate of 3.7 % each year. We captured the data into EPI DATA 3.1 and analysed it using STATA version 12.
We accessed 15,499 records and analysed 1167 records that were of children below 15 years old. The child TB cases represented 7.5 % (7.3 in 2009 & 7.6 % in 2010) of all the registered cases in Kampala district. The females were 47 % and the median age was 4 years (IQR 1, 10). The percent of children less than 5 years old was 54 %. The percent of pulmonary TB cases was 89 % (1041/1167) with 15 % smear positive. The proportion of extra-pulmonary TB cases was 11 % (126/1167). Among those that tested for HIV, 60 % (359/620) had test results available with an HIV co-infection rate of 47 % (168/359). Antiretroviral treatment uptake was 24 % among the co-infected. The incidence of child TB in Kampala was 56 (95 % CI 50–62) per 100,000 in 2009 and 44 (95 % CI 40–49) per 100,000 in 2010. Most of the TB cases (60 % (410/685)) in Kampala live in slum areas.
There was a higher child TB incidence of 56 per 100,000 in 2009 compared with 44 per 100,000 in 2010. The percentage of child TB cases was much higher at 7.5 % of all the reported TB cases than the WHO reported national average. For the review period, the TB cases clustered in particular slums in Kampala district.
We determined prevalence of pertussis infection and its associated host and environmental factors to generate information that would guide strategies for disease control.
In a cross-sectional study, 449 children aged 3 months to 12 years with persistent cough lasting ≥14 days were enrolled and evaluated for pertussis using DNA polymerase chain reaction (PCR) and ELISA serology tests.
Pertussis prevalence was 67 (15% (95% Confidence Interval (CI): 12–18)) and 81 (20% (95% CI: 16–24)) by PCR and ELISA, respectively among 449 participating children. The prevalence was highest in children with >59 months of age despite high vaccination coverage of 94% in this age group. Study demographic and clinical characteristics were similar between pertussis and non-pertussis cases. Of the 449 children, 133 (30%) had a coughing household member and 316 (70%) did not. Among 133 children that had a coughing household member, sex of child, sharing bed with a coughing household member and having a coughing individual in the neighborhood were factors associated with pertussis. Children that had shared a bed with a coughing household individual had seven-fold likelihood of having pertussis compared to children that did not (odds ratio (OR) 7.16 (95% CI: 1.24–41.44)). Among the 316 children that did not have a coughing household member, age <23 months, having or contact with a coughing individual in neighborhood, a residence with one room, and having a caretaker with >40 years of age were the factors associated with pertussis. Age <23months was three times more likely to be associated with pertussis compared to age 24–59 months (OR 2.97 (95% CI: 1.07–8.28)).
Findings suggest high prevalence of pertussis among children with persistent cough at a health facility and it was marked in children >59 months of age, suggesting the possibility of waning immunity. The factors associated with pertussis varied by presence or absence of a coughing household member.
HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18 month outcomes.
Randomized, placebo-controlled trial in four African countries. Infant diagnostic HIV testing was done regularly from birth, through 18 months. Kaplan-Meier analysis was used to assess 18 month cumulative infant HIV infection, HIV infection/or death and mortality rates.
Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower, among infants receiving daily NVP from 6 weeks to 6 months 1.1% (95% CI 0.2-1.8%), compared to placebo: 2.4% (95% CI 1.3-2.6%), p=0.049; but not significantly lower thereafter. Eighteen month postnatal infection rates were low: 2.2% [95% CI 1.1-3.3%] versus 3.1% [95% CI 1.9-4.4%], respectively, p=0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18 month postnatal infection rates (0.5%, 95% CI 0.0-1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI 1.9-5.5%); and infants of mothers with CD4 >350/mm3 not receiving ART (4.8%, 95% CI 2.7-6.8%), (p=0.46). There were no differences in adverse events between study arms.
This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age six weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.
nevirapine; infant HIV prophylaxis; PMTCT
Maternal-to-child-transmission of HIV-1 infection remains a significant cause of HIV-1 infection despite successful prevention strategies. Testing protective HIV-1 vaccines remains a critical priority. The immunogenicity of ALVAC-HIV vCP1521 (ALVAC) in infants born to HIV-1 infected women in Uganda was evaluated in the first pediatric HIV-1 vaccine study in Africa.
HPTN 027 was a randomized, double blind, placebo-controlled phase I trial to evaluate the safety and immunogenicity of ALVAC in 60 infants born to HIV-1 infected mothers with CD4 counts > 500 cell/μL that were randomized to the ALVAC vaccine or placebo. ALVAC-HIV vCP1521 is an attenuated recombinant canarypox virus expressing HIV-1 clade E env, clade B gag and protease gene products.
Infants were vaccinated at birth, 4, 8 and 12 weeks of age with ALVAC or placebo. Cellular and humoral immune responses were evaluated using IFN-γ ELISpot, CFSE proliferation, intracellular cytokine staining, binding and neutralizing antibody assays. Fisher's exact test was used to compare positive responses between study arms.
Low levels of antigen specific CD4 and CD8 T cell responses (intracellular cytokine assay) were detected at 24 months (CD4 – 6/36 vaccine vs. 1/9 placebo; CD8 – 5/36 vaccine vs. 0/9 placebo) of age. There was a non-significant trend toward higher cellular immune response rates in vaccine recipients compared to placebo. There were minimal binding antibody responses and no neutralizing antibodies detected.
HIV-1 exposed infants are capable of generating low levels of cellular immune responses to ALVAC vaccine, similar to responses seen in adults.
HIV vaccine; infants; immunogenicity; Africa; HIV prevention
Despite the recent innovations in tuberculosis (TB) and multi-drug resistant TB (MDR-TB) diagnosis, culture remains vital for difficult-to-diagnose patients, baseline and end-point determination for novel vaccines and drug trials. Herein, we share our experience of establishing a BSL-3 culture facility in Uganda as well as 3-years performance indicators and post-TB vaccine trials (pioneer) and funding experience of sustaining such a facility.
Between September 2008 and April 2009, the laboratory was set-up with financial support from external partners. After an initial procedure validation phase in parallel with the National TB Reference Laboratory (NTRL) and legal approvals, the laboratory registered for external quality assessment (EQA) from the NTRL, WHO, National Health Laboratories Services (NHLS), and the College of American Pathologists (CAP). The laboratory also instituted a functional quality management system (QMS). Pioneer funding ended in 2012 and the laboratory remained in self-sustainability mode.
The laboratory achieved internationally acceptable standards in both structural and biosafety requirements. Of the 14 patient samples analyzed in the procedural validation phase, agreement for all tests with NTRL was 90% (P <0.01). It started full operations in October 2009 performing smear microscopy, culture, identification, and drug susceptibility testing (DST). The annual culture workload was 7,636, 10,242, and 2,712 inoculations for the years 2010, 2011, and 2012, respectively. Other performance indicators of TB culture laboratories were also monitored. Scores from EQA panels included smear microscopy >80% in all years from NTRL, CAP, and NHLS, and culture was 100% for CAP panels and above regional average scores for all years with NHLS. Quarterly DST scores from WHO-EQA ranged from 78% to 100% in 2010, 80% to 100% in 2011, and 90 to 100% in 2012.
From our experience, it is feasible to set-up a BSL-3 TB culture laboratory with acceptable quality performance standards in resource-limited countries. With the demonstrated quality of work, the laboratory attracted more research groups and post-pioneer funding, which helped to ensure sustainability. The high skilled experts in this research laboratory also continue to provide an excellent resource for the needed national discussion of the laboratory and quality management systems.
Electronic supplementary material
The online version of this article (doi:10.1186/1478-4505-13-4) contains supplementary material, which is available to authorized users.
Acceptable quality standards; Biosafety level 3; Feasibility; Resource limited countries; TB culture
To describe five year growth, survival and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012.
All study children who were alive at eighteen months of age were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every six months from 24 to 60 months. At each visit, history, physical exam and growth measures were taken. From these measurements Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis.
528 study children were alive at age 18 months, and 491 (426 HIV uninfected; 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable to WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the two study arms were similar.
Both infected and uninfected children in the five-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource limited settings. Likewise, the low five year survival among HIV infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.
The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) for prevention mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from Phase I, randomized, double blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV-1-infected women in Uganda are reported.
HIV exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8 and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination, and days 1 and 2 post-vaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA PCR.
From October 2006 to May 2007, 60 infants (48 vaccine, 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by Diptheria, Polio, Hepatitis B and Heamophilus influenzae type B and measles vaccination were similar in the two arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine, 1 placebo) and one in vaccine arm at 2 weeks of age].
The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high quality infant HIV vaccine trials is achievable in Africa.
HIV vaccine; ALVAC; infants; Africa; breast milk transmission
As part of site development for clinical trials in novel TB vaccines, a cohort of infants was enrolled in eastern Uganda to estimate the incidence of tuberculosis. The study introduced several mortality reduction strategies, and evaluated the mortality among study participants at two years. The specific of objective of this sub-study was to estimate 2 year mortality and associated factors in this community-based cohort.
A community based cohort of 2500 infants was enrolled from birth up to 8 weeks of age and followed for 1–2 years. During follow up, several mortality reduction activities were implemented to enhance cohort survival and retention. The verbal autopsy process was used to assign causes of death.
A total of 152 children died over a median follow up period of 2.0 years. The overall crude mortality rate was 60.8/1000 or 32.9/1000 person years with 40 deaths per 1000 for children who died in their first year of life. Anaemia, malaria, diarrhoeal diseases and pneumonia were the top causes of death. There was no death directly attributed to tuberculosis. Significant factors associated with mortality were young age of a mother and child’s birth place not being a health facility.
The overall two year mortality in the study cohort was unacceptably high and tuberculosis disease was not identified as a cause of death. Interventions to reduce mortality of children enrolled in the cohort study did not have a significant impact. Clinical trials involving infants and young children in this setting will have to strengthen local maternal and child health services to reduce infant and child mortality.
Mortality; Infants; Factors associated with mortality; Verbal autopsy
A pooled analysis of individual data from >5000 human immunodeficiency virus type 1 (HIV-1)–infected mothers and their infants from Africa and India who participated in 5 randomized trials shows that extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection.
Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission.
Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks.
Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%–80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%–69%; P < .001).
Conclusions. Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
breast milk; HIV; nevirapine
We used a novel high resolution melting (HRM) diversity assay to analyze HIV diversity in Ugandan children (ages 0.6 to 12.4 years) who were enrolled in an observational study of antiretroviral treatment (ART). Children were maintained on ART if they were clinically and immunologically stable.
HIV diversity was measured prior to ART (baseline) in 76 children and after 48 or 96 weeks of ART in 14 children who were not virally suppressed. HIV diversity (expressed as HRM scores) was measured in six regions of the HIV genome (two in gag, one in pol, three in env).
Higher baseline HRM scores were significantly associated with older age (≥ 2 years, P ≤ 0.001 for all six regions). HRM scores from different regions were weakly correlated. Higher baseline HRM scores in three regions (one in gag, two in env) were associated with ART failure. HIV diversity was lower in four regions (two in gag, one in pol, one in env) after 48 to 96 weeks of non-suppressive ART compared to baseline.
Higher levels of HIV diversity were observed in older children prior to ART and higher levels of diversity in some regions of the HIV genome were associated with ART failure. Prolonged exposure to non-suppressive ART was associated with a significant decrease in viral diversity in selected regions of the HIV genome.
HIV; diversity; children; antiretroviral therapy
The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12–18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents.
In a prospective cohort study, we recruited 5000 adolescents and followed them actively, every 6 months, for 1–2 years. Participants suspected of having TB were those who had any of; TB signs and symptoms, history of TB contact or a positive tuberculin skin test (TST) of ≥10 mm. Laboratory investigations included sputum smear microscopy and culture.
Of the 5000 participants, eight culture confirmed cases of TB were found at baseline: a prevalence of 160/100,000 (95% confidence interval (CI), 69–315). There were 13 incident TB cases detected in an average of 1.1 person years: an incidence of 235/100,000 person years (95% CI, 125–402). None of the confirmed TB cases were HIV infected. Predictors for prevalent TB disease were: a history of TB contact and a cough ≥ 2 weeks at baseline and being out of school, while the only predictor for incident TB was a positive TST during follow-up.
The TB incidence among adolescents in this rural part of Uganda seemed too low for a phase III TB vaccine trial. However, the study site demonstrated capability to handle a large number of participants with minimal loss to follow-up and its suitability for future clinical trials. Improved contact tracing in TB program activities is likely to increase TB case detection among adolescents. Future studies should explore possible pockets of higher TB incidence in urban areas and among out of school youth.
The benefits of long-term antiretroviral therapy (ART) are recognized all over the world with infected children maturing into adults and HIV infection becoming a chronic illness. However, the improved survival is associated with serious metabolic complications, including lipodystrophy (LD), dyslipidemia, insulin resistance, lactic acidosis and bone loss. In addition, the dyslipidemia mainly seen with protease inhibitors may increase the risk of cardiovascular disease in adulthood and potentially in children as they mature into adults. Nucleoside reverse transcriptase inhibitors, particularly stavudine, zidovudine and didanosine are linked to development of LD and lactic acidosis. Perinatally infected children initiate ART early in life; they require lifelong therapy with multiple drug regimens leading to varying toxicities, all potentially impacting their quality of life. LD has a significant impact on the mental health of older children and adolescents leading to poor self-image, depression and subsequent poor adherence to therapy. Reduced bone mineral density (BMD) is reported in both adults and children on ART with the potential for children to develop more serious bone complications than adults due to their rapid growth spurts and puberty. The role of vitamin D in HIV-associated osteopenia and osteoporosis is not clear and needs further study. Most resource-limited settings are unable to monitor lipid profiles or BMD, exposing infected children and adolescents to on-going toxicities with unclear long-term consequences. Improved interventions are urgently needed to prevent and manage these metabolic complications. Longitudinal cohort studies in this area should remain a priority, particularly in resource-limited settings where the majority of infected children reside.
children; adolescents; HIV; antiretroviral therapy; metabolic complications; cardiovascular disease
There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.
Antiretroviral therapy (ART) is known to save lives. Among HIV-infected infants living in resource constrained settings, the short and long term benefits of ART are only partially known. This study was designed to determine the virologic, immunologic and clinical outcomes of antiretroviral therapy in a cohort of HIV-infected infants receiving care from an outpatient clinic in Kampala, Uganda.
A prospective cohort of HIV-infected infants receiving treatment at the Baylor-Uganda clinic was analyzed. Patients were diagnosed, enrolled and followed up at the clinic. HIV viral load, CD4 cell counts and clinical progress were assessed during follow-up. Descriptive statistical analysis and logistic regression modeling to determine predictors of treatment success were conducted.
Of 91 HIV-infected infants enrolled into the cohort, 53 (58.2%) infants were female; 43 (47.3%) were 6 months of age or younger, and 50 (55.6%) had advanced HIV/AIDS disease (Clinical stage 3 or 4). Eighty four infants started ART and 78 (92.9%) completed 6 months of treatments. Fifty six (71.8%) infants attained virologic suppression by month-6 of ART, and at month-12 of ART, the cumulative probability of attaining viral suppression was 83.1%. None of the baseline infant factors (age, sex, WHO stage, CD4 cell percent, weight for age, or height for age z-score) predicted treatment success. There was an increase in CD4 cells from a baseline mean of 23% to 30% at month-6 of treatment (p<0.001) and by month-24 of ART, the mean CD4 percent was 36%. A total of 7 patients died while on ART and another 7 experienced adverse events that were related to treatment.
Our results show that, even among very young patients from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe. However, baseline characteristics do not predict recovery in this age group.
Infant; HIV; Antiretroviral therapy; Mortality; Malnutrition
In resource-rich countries, bolus fluid expansion is routinely used for the treatment of poor perfusion and shock, but is less commonly used in many African settings. Controversial results from the recently completed FEAST (Fluid Expansion As Supportive Therapy) trial in African children have raised questions about the use of intravenous bolus fluid for the treatment of shock. Prior to the start of the trial, the Independent data monitoring committee (IDMC) developed stopping rules for the proof of benefit that bolus fluid resuscitation would bring. Although careful safety monitoring was put in place, there was less expectation that bolus fluid expansion would be harmful and differential stopping rules for harm were not formulated.
In July 2010, two protocol amendments were agreed to increase the sample size from 2,880 to 3,600 children, and to increase bolus fluid administration. There was a non-significant trend against bolus treatment, but although the implications were discussed, the IDMC did not comment on the results, or on the amendments, in order to avoid inadvertent partial unblinding of the study.
In January 2011, the trial was stopped for futility, as the combined intervention arms had significantly higher mortality (relative risk 1.46, 95% CI 1.13 to 1.90, P = 0.004) than the control arm. The stopping rule for proof of benefit was not achieved, and the IDMC stopped the trial with a lower level of significance (P = 0.01) due to futility and an increased risk of mortality from bolus fluid expansion in children enrolled in the trial. The basis for this decision was that the local standard of care was not to use bolus fluid for the care of children with shock in these African countries, and this was a different standard of care to that used in the UK. These decisions emphasize two important principles: firstly, the IDMC should avoid inadvertent unblinding of the trial by commenting on amendments, and secondly, when considering stopping a trial, the IDMC should be guided by the local standard of care rather than standards of care in other parts of the world.
The diagnosis of childhood tuberculosis remains a challenge worldwide. The Xpert MTB/RIF test, a rapid mycobacteria tuberculosis diagnostic tool, was recommended for use in children based on data from adult studies. We evaluated the performance of the Xpert MTB/RIF test for the diagnosis of childhood pulmonary tuberculosis using one induced sputum sample and described clinical characteristics associated with a positive Xpert MTB/RIF test. The sputum culture on both Lowenstein-Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) was the gold standard.
We consecutively enrolled 250 Ugandan children aged 2 months to 12 years with suspected pulmonary tuberculosis between January 2011 and January 2012 into a cross-sectional diagnostic study at a tertiary care facility in Uganda.
We excluded data from 15 children (13 contaminated culture and 2 indeterminate MTB/RIF test results) and analysed 235 records. The Xpert MTB/RIF test had a sensitivity of 79.4% (95% CI 63.2 - 89.7) and a specificity of 96.5% (95% CI 93 – 98.3). The Xpert MTB/RIF test identified 13 of the 14 (92.9%) smear positive-culture positive and 14 of the 20 (70%) smear negative -culture positive cases. The Xpert MTB/RIF identified twice as many cases as the smear microscopy (79.4% Vs 41.2%). Age > 5 years (OR 3.3, 95% CI 1.4 – 7.4, p value 0.005), a history of Tuberculosis (TB) contact (OR 2.4, 95% CI 1.1 – 5.2, p value 0.03), and a positive tuberculin skin test (OR 4.1, 95% CI 1.7 – 10, p value 0.02) was associated with a positive Xpert MTB/RIF test. The median time to TB detection was 49.5 days (IQR 38.4-61.2) for LJ, and 6 days (IQR 5 – 11.5) for MGIT culture and 2 hours for the Xpert MTB/RIF test.
The Xpert MTB/RIF test on one sputum sample rapidly and correctly identified the majority of children with culture confirmed pulmonary tuberculosis with high specificity.
Children; Pulmonary tuberculosis; Sensitivity; Specificity; Xpert MTB/RIF