MUUCSF Presentations

International AIDS Society (IAS)
Please click on conference to view abstracts presented.


2012, WASHINGTON DC, USA

Mwesigwa J, Cohan DL, Plenty A, Charlebois ED, Ruel T, Ades V, Clark TD, Natureeba P, Achan J, Kamya MR, Havlir DV, Gandhi M. Lopinavir and Efavirenz Concentrations in Paired Hair Samples as a Marker of Cumulative Exposure among Postpartum Women and Breastfeeding Infants in Tororo, Uganda. Abstract presented at IAS July 2012

 

Background: As increasing numbers of African women receive antiretrovirals (ARVs) during breastfeeding, understanding kinetics of ARV transfer to infants through breast milk is critical. ARV levels in plasma or breast milk reflect exposure over short time intervals. By contrast, ARV levels in hair samples measure cumulative exposure over weeks-months and are strongly associated with outcomes in treated individuals. We measured hair concentrations of ARVs in HIV-infected mothers receiving ARVs and their infants after 12 weeks of breastfeeding in Tororo, Uganda

 

Methods: As part of the Prevention of Malaria and HIV disease in Tororo (PROMOTE) study, HIV-infected pregnant women were randomized to lopinavir/ritonavir-based or efavirenz-based therapy. At 12 weeks postpartum, ~20 strands of hair were collected from mothers and infants and ARV concentrations measured using liquid chromatography/tandem mass spectrometry. The ratios of infant:maternal concentrations were calculated for each drug and Spearman correlations between infant adverse events and hair ARV concentrations were examined.

 

Results: As of September 2011, 268 pregnant women had been enrolled with 259 infants born. All infants were HIV-negative at 12 weeks. We collected small hair samples from 45 mother-infant pairs on lopinavir/ritonavir and 64 on efavirenz at 12 weeks and found infant/maternal hair concentration ratios of 0.867 for lopinavir and 0.396 for efavirenz (Table). There was no significant correlation between infant hair levels of ARVs and adverse effects.


Conclusions: We report for the first time the kinetics of ARV transfer from mother to infant during breastfeeding by assessing levels of ARVs in paired hair samples. Cumulative infant exposure to lopinavir during breastfeeding was much higher than exposure to efavirenz as assessed by hair concentrations (87% transfer versus 40%) with equal rates of protection from HIV acquisition. Further work to correlate cumulative infant exposure to ARVs via breastfeeding and toxicities is needed.


Achan J, Parikh S, Kakuru A, Ikilezi G, Ruel T, Mwebaza N, Clark TD, Dorsey G, Charlebois ED, Rosenthal PJ, Kamya MR, Havlir DV, Aweeka F. Relationship between lumefantrine exposure, ART regimen and risk of malaria following treatment for uncomplicated malaria in HIV infected children in rural Uganda. Abstract presented at IAS July 2012

 

Background: Treatment of malaria in HIV infected individuals presents a challenge due to potential drug-drug interactions. We previously reported a 40% reduction in malaria incidence in HIV infected children receiving LPV/r; attributable to drug interactions and prolonged lumefantrine (LR) exposure following malaria treatment with artemether-lumefantrine (AL). We conducted further analysis to determine the impact of ART regimen and lumefantrine exposure on risk of recurrent malaria, recurrent and asymptomatic parasitemia, and gametocytemia.

 

Methods: Patients received either LPV/r or NNRTI-based (NVP or EFV) ART and were followed for 2 years. Uncomplicated malaria was treated with AL and capillary plasma LR PK measured on day 7 and 14 post-treatment. Study endpoints included LR exposure in the two arms, risk of recurrent malaria, recurrent and asymptomatic parasitemia and gametocytemia.

 

Results: Children aged 2 months to 6 years, experiencing 340 malaria episodes were followed from September, 2009 to July, 201. LR PK was done for 157 episodes. Median day 14 LR levels were higher in the LPV/r-based compared to the NNRTI-based arm (340 vs. 58 ng/mL, p<0.0001). In the NNRTI-arm, day 14 LR levels >50ng/ml were associated with a 72% reduction in risk of recurrent malaria after 63 days compared to levels <50 ng/mL (p=0.04). In both arms, risk for recurrent parasitemia at 28 days was significantly reduced when Day 7 and 14 concentrations exceeded 300 and 50 ng/mL, respectively (HR 0.17-0.25). All children in the PI arm had LR levels >50 ng/mL at day 14. Children receiving LPV/r also had a lower risk of patent gametocytemia at the time malaria is diagnosed (6.7% vs. 14.6%, p = 0.03) and during the 28 days following malaria (2.5% vs.5.6%, p = 0.045) compared to those receiving NNRTIs. There was no association between ART arm and the risk of asymptomatic parasitemia.

 

Conclusions: Increased lumefantrine exposure in patients receiving LPV/r based ART was associated with a reduction in risk of recurrent malaria following treatment and a lower risk of gametocytemia. These findings highlight the importance of characterizing interactions between ARTs and antimalarial drugs.


Ades V, Mwesigwa J, Natureeba P, Clark TD, Plenty A, Ruel T, Charlebois ED, Achan J, Kamya MR, Havlir DV, Cohan DL. Neonatal Death in Premature HIV-exposed Infants Born to Women on Antiretroviral Therapy in Rural Uganda. Abstract presented at IAS July 2012

 

Background: Neonatal death rates are high in low-resource settings, but gestational age (GA) measurement is often imprecise. Studies of neonatal outcomes with accurate GA information are needed to better characterize predictors of poor perinatal outcomes.

 

Methods: This was a secondary analysis of a randomized clinical trial of HIV-infected pregnant women in Uganda (NCT00993031). Subjects at 12-28 weeks gestation were randomized to antiretroviral therapy (ART) with either Efavirenz or Lopinavir/ritonavir. GA was established using last menstrual period (LMP) and sonographic biometry. Basic resuscitation methods with oxygen were available, and infants were followed every two weeks in the study clinic. Perinatal and neonatal death were defined as death of a live-born infant within the first 7 and 28 days of life, respectively. Logistic regression was used to identify predictors of death.

 

Results: Of 213 live-born infants, none were less than 29 weeks, all tested HIV negative at birth and 12 neonates died (5.6%). Of 11 infants born at 29-31 weeks, 5 (45%) survived the neonatal period. At 32-36 weeks, 38 of 40 neonates (95%) survived. In univariate analysis, GA, birthweight, gravidity, Apgar scores and mother’s duration of ART were significantly associated with neonatal death. In the multivariable model adjusting for infant sex, maternal age and treatment arm, only GA (OR=0.44, CI 0.32-0.61) and 1-minute Apgar score (OR=0.17, CI=0.04-0.73) predicted neonatal death.

 

Conclusions: The neonatal death rate in this cohort of HIV-exposed infants is 44 in 1000 live births. GA is strongly associated with neonatal survival. Premature infants born in low-resource settings are at high risk of neonatal death, even with resuscitation and access to medical care. Infants born under 32 weeks are at highest risk of death; however, infants at 32-36 weeks have a good chance of neonatal survival.


Young SL, Natamba BK, Luwedde F, Plenty A, Mwesigwa J, Natureeba P, Osterbauer B, Achan J, Clark TD, Ades V, Nzarubara B, Ruel T, Kamya MR, Charlebois ED, Havlir DV, Cohan DL. Severe household food insecurity is highly prevalent and associated with suboptimal breastfeeding practices among HIV-infected women in rural Uganda. Abstract presented at IAS July 2012

 

Background: Ugandan guidelines recommend 6 months of exclusive breastfeeding (EBF) for HIV-infected women with continued breastfeeding (BF) for at least 1 year. Food insecurity has been posited to be a barrier to adherence to infant feeding recommendations. We therefore explored if greater food insecurity was associated with sub-optimal breastfeeding (BF) practices.

 

Methods: Data on food insecurity and BF practices and beliefs were collected among HIV-infected pregnant and BF women on antiretroviral therapy (ART) participating in the PROMOTE trial (NCT00993031) in Tororo, Uganda. Food insecurity was assessed using the Household Food Insecurity Access Scale (HFIAS). BF practices were determined using monthly maternal reports from a prospective cohort of 143 PROMOTE infants born between March 6, 2010 and October 9, 2011. Beliefs about food insecurity and BF were assessed using a purposive sample of 32 BF PROMOTE subjects who participated in in-depth interviews (IDIs) in July and August 2011.

 

Results: Food insecurity was very high; 82.5% were from severely, 14.7% moderately, and 2.1% mildly food insecure households. Median (inter-quartile range) HFIAS score was 17 (12-22). The prevalence of EBF was 89.5% and 66.9% at 3 and 6 months respectively; the prevalence of BF at 12 months was 84.1%. In multivariate logistic regression adjusting for socio-demographics and HIV-stage, the odds (95% confidence interval) of EBF at 6 months was 0.16 (0.03-0.86) for women in severely food insecure households compared to those in non-severely food insecure households. Consistent with this, IDIs revealed that BF participants associated insufficient nutritional intake with difficulties adhering to infant feeding recommendations: 78.1% were concerned about adequate breast milk production and 46.9% reported experiencing problems while EBF, e.g. unsatisfied baby.

 

Conclusions: Severe food insecurity is associated with suboptimal EBF. The mitigation of food insecurity may increase the duration of EBF among HIV+ women in rural Uganda.


Chamie G, Kwarisiima D, Clark TD, Kabami J, Jain V, Geng E, Petersen ML, Thirumurthy H, Kamya MR, Havlir DV, Charlebois ED, SEARCH Consortium. Integrated Community HIV Testing Campaigns: Leveraging HIV infrastructure for non- communicable diseases. Oral abstract at IAS, July 2012.

 

Background: The high burden of undiagnosed HIV in sub-Saharan Africa limits treatment and prevention efforts. Community-based HIV testing campaigns can address this challenge and provide an untapped opportunity to identify non-communicable diseases (NCDs). We tested the feasibility and diagnostic yield of integrating NCD and communicable diseases into a rapid HIV testing and referral campaign for all residents of a rural Ugandan parish.

 

Methods: A five-day, multi-disease campaign, offering diagnostic, preventive, treatment and referral services, was performed in May 2011. Services included point-of-care screening for HIV, malaria, TB, hypertension and diabetes. Finger-prick diagnostics eliminated the need for phlebotomy. HIV infected adults met clinic staff and peer counselors on-site; those with CD4≤100/μL underwent intensive counseling and rapid referral for antiretroviral therapy (ART). Community participation, case-finding yield, and linkage to care three months post-campaign were analyzed.

 

Results: Of 6,300 residents, 2,323/3,150 (74%) adults and 2,020/3,150 (69%) children participated. An estimated 95% and 52% of adult female and male residents participated respectively. Adult HIV prevalence was 7.8%, with 46% of HIV-infected adults newly diagnosed. Thirty-nine percent of new HIV diagnoses linked to care. In a pilot subgroup with CD4≤100, 83% linked and started ART within 10 days. Malaria was identified in 10% of children, and hypertension and diabetes in 28% and 3.5% of adults screened, respectively. Sixty-five percent of hypertensives and 23% of diabetics were new diagnoses, of which 43% and 61% linked to care, respectively. Screening identified suspected TB in 87% of HIV-infected and 19% of HIV-uninfected adults; 52% percent of HIV-uninfected TB suspects linked to care.

 

Conclusions: In an integrated campaign engaging 74% of adult residents, we identified a high burden of undiagnosed HIV, hypertension and diabetes. Improving male attendance and optimizing linkage to care require new approaches. The campaign demonstrates the feasibility of integrating hypertension, diabetes and communicable diseases into HIV initiatives.


Jain V, Byonanebye D, Muhaawe J, Kabami J, Black D, Clark TD, Chamie G, Geng E, Thirumurthy H, Rooney J, Charlebois ED, Amanyire G, Havlir DV, Kamya MR, SEARCH Consortium. Patient attitudes toward initiating early antiretroviral therapy at high CD4+ cell counts above national guideline thresholds. Poster presentation at IAS, July 2012.

 

Background: As evidence mounts favoring earlier antiretroviral therapy (ART) initiation, understanding patient attitudes towards initiating ART at high CD4 counts in Sub-Saharan Africa above guideline thresholds is important: little is known about why patients might opt for therapy if eligible while still healthy and asymptomatic. Within a trial in Uganda evaluating the efficacy and cost of early ART initiation at high CD4 counts, we assessed patient attitudes towards starting ART.

 

Methods: Patients receiving HIV care but not yet eligible for ART in a rural Western Ugandan clinic (CD4>250 in 2011) were screened for a study assessing ART initiation prior to guideline eligibility (EARLI Study: NCT01479634). Inclusion criteria were CD4>250 (no CD4 upper limit), no WHO stage 3/4 conditions, and no prior ART. A systematic survey was conducted at study enrollment, prior to ART. Eight questions explored reasons for consenting to early ART, and the proportion of respondents identifying each reason was tabulated. No enrollment incentives were provided.

 

Results: Of 112 patients screened, 98 were eligible for entry and 94/98 (96%) chose to enroll and initiate ART (n=20 with CD4 250-350, and n=74 with CD4>350). Median CD4 among ART initiators was 506 (IQR 354-669). The most prevalent reasons given for initiating early ART related to preserving health and productivity: 87% cited a desire to stay healthy, 53% to continue working, and 52% to continue caring for family. Secondary reasons included avoiding transmission to others (29%) or to children (26% of females). Finally, 9% cited feeling unwell, and 7% cited their spouse/partner was taking ART as reasons for enrolling.

 

Conclusions: In healthy patients successfully linked to HIV care with high CD4 counts (median CD4=506), we observed very strong interest in initiating ART if available. Preserving health and economic productivity, and avoiding transmission, were key reasons for seeking early ART at high CD4 counts.


Namusobya J, Jain V, Chamie G, Kabami J, Clark TD, Charlebois ED, Havlir DV, Kamya MR, Geng E, for the SEARCH Collaboration. Retention in care, lost-to-follow-up, and mortality among HIV infected patients who enroll in care with CD4 levels >350/µl in Uganda. Poster presentation at IAS, July 2012.

 

Background: Retention in care for HIV patients in Africa who present with CD4 levels above 350/µL (i.e., the treatment threshold) is needed for appropriate monitoring and timely ART initiation. To date most studies are restricted to patients already on ART and do not account for outcomes among the lost to follow-up (LTF).

 

Methods: We evaluated adults with an entry CD4 level >350/µL and at least one clinic visit between October 1, 2008 and October 1, 2010 at an urban and a rural HIV/AIDS clinic in Uganda operated by the Mulago Mbarara Joint AIDS Program. A 15% random sample of LTF patients – defined as nine months absence from clinic – was intensively tracked in the community. Probability weights were used to incorporate tracking outcomes with cumulative incidence estimates in the entire clinic population using a competing risk approach.

 

Results: Of 6,711 patients, 71% were women, the median age was 29 years (IQR: 25-35), and median entry CD4 level was 546/µL (IQR: 433-717), 1,294 patients became LTF (19%); a random sample of 206 (16%) were tracked; and in 175 (85%) outcomes were successfully ascertained. Sample-corrected estimates for the clinic population entering with CD4 levels above treatment thresholds show that two years after enrollment 24.8% started ART (95% Cl: 22.2-24.7), 1.6% died (95% Cl: 1.2-1.9), 8.1% were not seeking care (95% Cl: 7.3-8.8), and the remaining 65.5% of patients remained in care at one of 26 HIV care programs in the area.

 

Conclusions: Accounting for outcomes among the lost produces a more informative understanding of the effectiveness of routine HIV services for clinic populations who enter care above treatment thresholds than previously available. Retention in care within the network of HIV care sites is substantially higher than clinic retention. A substantial sub-population, however, were not seeking care and deaths were nearly twice population mortality rates.


Jain V, Kwarisiima D, Liegler T, Clark TD, Chamie G, Kabami J, Black D, Amanyire G, Byonanebye D, Geng E, Thirumurthy H, Petersen ML, Charlebois ED, Kamya MR, Havlir DV, and the SEARCH Collaboration. Changes in population-level HIV RNA distribution one year after implementation of key components of an HIV ‘test and treat’ strategy in rural Uganda. Latebreaker oral abstract at IAS, July 2012.

 

Background: 'Test-and-treat' programs combining expanded HIV diagnosis, linkage to care, and ART delivery are under consideration, but real-world experience is lacking. During 2011, in rural southwestern Uganda, implementation of ART eligibility to CD4< 350/uL began. Concomitantly, we (A) conducted a community-wide HIV testing/linkage-to-care campaign, and (B) offered ART to adults with CD4≥350 via a research study (EARLI: NCT01479634). One year later, we conducted a second health campaign and examined the population distribution of HIV RNA levels.

 

Methods: During weeklong campaigns in May 2011 and 2012, all Kakyerere Parish residents were offered HIV testing (Determine, Inverness) in multi-disease diagnosis and linkage “health fairs”. In HIV+ individuals, HIV RNA levels were measured by a validated fingerprick blood collection method and RT-PCR (Abbott). We assessed population HIV RNA levels by computing (1) the proportion of persons with an undetectable VL, (2) the median VL, and (3) the mean log(VL) among HIV+ persons.

 

Results: After community mobilization, 4,343 and 4,872 persons attended the 2011 and 2012 campaigns, respectively. We estimated 69% and 71% community participation based on census data from 2011 and 2012, respectively. Adult HIV prevalence (≥18yrs.) was 7.8% in 2011 (179/2,282 adults) and 9.4% in 2012 (210/2271 adults). Prevalence was 18.6% on the final day of the health fair located at the parish trading center, and 8.2% across prior days (p< 0.001). A substantially higher proportion of HIV+ individuals had an undetectable HIV RNA level in 2012 vs. 2011 (55% vs. 37%), and both median VL and mean log(VL) were lower in 2012 (see table).
Conclusions: In this ongoing study, we demonstrate that key components of a test-and-treat strategy are feasible in a resource-limited setting. One year after implementing intensified community-based HIV testing and linkage, with ART eligibility regardless of CD4 count, over half of HIV+ persons attending a health campaign had undetectable HIV RNA.


Thirumurthy H, Chamie G, Kabami J, Jain V, Clark TD, Kwarisiima D, Geng E, Petersen ML, Kamya MR, Charlebois ED, Havlir DV, and the SEARCH Collaboration. Improved employment and children's education outcomes in households of HIV-positive adults with high CD4 counts: evidence from a community-wide health campaign in Uganda. Upcoming oral abstract at IAS, July 2012.

 

Background: Despite growing evidence that socio-economic outcomes among HIV-infected adults show improvement after antiretroviral therapy (ART) initiation, little is known about the variation in these outcomes among a population that also includes individuals with high CD4 counts and those not enrolled in care. We examined associations between CD4 count and socio-economic outcomes among adults participating in a community-wide health campaign in a rural Ugandan parish.

 

Methods: A one-week community health campaign offering diagnostic and treatment services for HIV and other infectious and non-communicable diseases was conducted in May 2011. Data on campaign participants´ employment were collected, and a detailed household socio-economic survey was conducted among a random subset of participants. Multivariable regression was used to assess relationships between CD4 count and employment and educational outcomes. Results: 2,323 adults (74% of the community) participated in the campaign. 179 adults (7.8%) tested HIV-positive and 46% were newly diagnosed. HIV-positive adult participants with CD4 >550 and 350-550 worked 4.8 and 5.3 more days during the past month than those with CD4 < 200 (p< 0.05). No differences in work patterns were found between participants with CD4 200-350 and < 200. The association was similar among those on ART and not on ART. Children's school enrollment was also associated with adults´ CD4 counts. Children in households of adults with CD4 >350 had 20% higher school enrollment rates than children in households of adults with CD4 < 200 (p< 0.05). Finally, socio-economic outcomes of HIV-participants with high CD4 counts resembled those of HIV-negative participants.

 

Conclusions: Outcomes of HIV-positive adults with high CD4 counts are not only better than those of adults with low CD4 counts, they also resemble those of HIV-negative adults. Early initiation of ART could generate economic benefits by preventing a decline in employment and education outcomes and maintaining them at levels seen among HIV-negative peers.

 

Jain V, Byonanebye D, Muhaawe J, Kabami J, Black D, Clark TD, Chamie G, Geng E, Thirumurthy H, Rooney J, Charlebois ED, Amanyire G, Havlir DV, Kamya MR, SEARCH Consortium. Patient attitudes toward initiating early antiretroviral therapy at high CD4+ cell counts above national guideline thresholds.Poster presentation at IAS, July 2012.

 

Background: As evidence mounts favoring earlier antiretroviral therapy (ART) initiation, understanding patient attitudes towards initiating ART at high CD4 counts in Sub-Saharan Africa above guideline thresholds is important: little is known about why patients might opt for therapy if eligible while still healthy and asymptomatic. Within a trial in Uganda evaluating the efficacy and cost of early ART initiation at high CD4 counts, we assessed patient attitudes towards starting ART.

 

Methods: Patients receiving HIV care but not yet eligible for ART in a rural Western Ugandan clinic (CD4>250 in 2011) were screened for a study assessing ART initiation prior to guideline eligibility (EARLI Study: NCT01479634). Inclusion criteria were CD4>250 (no CD4 upper limit), no WHO stage 3/4 conditions, and no prior ART. A systematic survey was conducted at study enrollment, prior to ART.
Eight questions explored reasons for consenting to early ART, and the proportion of respondents identifying each reason was tabulated. No enrollment incentives were provided.

 

Results: Of 112 patients screened, 98 were eligible for entry and 94/98 (96%) chose to enroll and initiate ART (n=20 with CD4 250-350, and n=74 with CD4>350). Median CD4 among ART initiators
was 506 (IQR 354-669). The most prevalent reasons given for initiating early ART related to preserving health and productivity: 87% cited a desire to stay healthy, 53% to continue working, and 52% to continue caring for family. Secondary reasons included avoiding transmission to others (29%) or to children (26% of females). Finally, 9% cited feeling unwell, and 7% cited their spouse/partner was taking ART as reasons for enrolling.

 

Conclusions: In healthy patients successfully linked to HIV care with high CD4 counts (median CD4=506), we observed very strong interest in initiating ART if available. Preserving health and economic productivity, and avoiding transmission, were key reasons for seeking early ART at high CD4 counts.

 

Namusobya J, Jain V, Chamie G, Kabami J, Clark TD, Charlebois ED, Havlir DV, Kamya MR, Geng E, for the SEARCH Collaboration.Retention in care, lost-to-follow-up, and mortality among HIV infected patients who enroll in care with CD4 levels >350/µl in Uganda. Poster presentation at IAS, July 2012.

 

Background: Retention in care for HIV patients in Africa who present with CD4 levels above 350/µL (i.e., the treatment threshold) is needed for appropriate monitoring and timely ART initiation. To date most studies are restricted to patients already on ART and do not account for outcomes among the lost to follow-up (LTF).

 

Methods: We evaluated adults with an entry CD4 level >350/µL and at least one clinic visit between October 1, 2008 and October 1, 2010 at an urban and a rural HIV/AIDS clinic in Uganda operated by the Mulago Mbarara Joint AIDS Program. A 15% random sample of LTF patients – defined as nine months absence from clinic – was intensively tracked in the community. Probability weights were used to incorporate tracking outcomes with cumulative incidence estimates in the entire clinic population using a competing risk approach.

 

Results: Of 6,711 patients, 71% were women, the median age was 29 years (IQR: 25-35), and median entry CD4 level was 546/µL (IQR: 433-717), 1,294 patients became LTF (19%); a random sample of 206 (16%) were tracked; and in 175 (85%) outcomes were successfully ascertained. Sample-corrected estimates for the clinic population entering with CD4 levels above treatment thresholds show that two years after enrollment 24.8% started ART (95% Cl: 22.2-24.7), 1.6% died (95% Cl: 1.2-1.9), 8.1% were not seeking care (95% Cl: 7.3-8.8), and the remaining 65.5% of patients remained in care at one of 26 HIV care programs in the area.

 

Conclusions: Accounting for outcomes among the lost produces a more informative understanding of the effectiveness of routine HIV services for clinic populations who enter care above treatment thresholds than previously available. Retention in care within the network of HIV care sites is substantially higher than clinic retention. A substantial sub-population, however, were not seeking care and deaths were nearly twice population mortality rates.

 

T. Ruel, J. Achan, W. Huang, H. Cao, P. Li, L.A. Eller, M. Killian, E. Sinclair, E. Charlebois, D.V. Havlir, J. Wong. XCR4-tropism is associated with the preferential establishment of an HIV-reservoir in naïve CD4+ T cells among HIV-positive Ugandan children receiving antiretroviral therapy

Background: Children have large populations of naive CD4+ T-cells that characteristically express high levels of CXCR4 and low levels of CCR5, compared to memory CD4+ T-cells. We hypothesized that HIV+ Ugandan children infected with CXCR4-tropic virus would exhibit larger HIV-DNA reservoirs in naïve CD4+ T-cells, compared to children infected with CCR5-tropic (R5) virus.


Methods: Cryopreserved PBMC from a convenience sample of 12 HIV+ Ugandan children receiving antiretroviral therapy (ART) with undetectable plasma HIV-RNA (< 400 copies/ml, Amplicor, Roche) were sorted into naïve (CD27+CD45RA+) and memory (CD27-CD45+ and CD45-CD27±) CD3+CD4+ T-cells. HIV-DNA levels were determined using a Taqman assay targeting gag, normalized to cellular-DNA content (tert, ABI). Co-receptor tropism was determined using a commercial phenotypic assay (Trophile, Monogram). We calculated 1) the ratio of the prevalence of infection (copies per 106 cells) in naïve to the prevalence in memory CD4+ T-cells and 2) the proportion of the total peripheral CD4+ T-cell HIV-reservoir that is contained in naïve CD4+ T-cells, and compared them between children with R5- and dual/mixed(CXCR4/CCR5, DM)-tropic virus using non-parametric statistics.

 

Results: Median age was 4.9 (interquartile range 3.5-8.1) years, CD4+T-cell number 743 cells/ul (565-1089), CD4+ T-cell percentage 25 (21-29), and ART duration 95 days (95-147), with 6 subjects each with HIV-envelope-subtypes A and D. R5 virus was identified in 8 and DM virus in 4 children.

 

 

HIV Copies /
10^6 Naïve CD4+ T-Cells

HIV Copies /
10^6 Memory CD4+ T-cells

Ratio of infection prevalence

HIV+ Naive CD4+ T-cells /
Total HIV+CD4+ T-cells

R5

2,962 (129-10,668)

9,931 (1037-11,808)

0.7 (0.2-4.3)

53% (25%-80%)

DM

14,733 (1,344-135,120)

930 (151-29,702)

8.9 (6.6-13.0)

92% (88%-95%)

P-value*

0.31

0.61

0.04

0.07

* Comparing R5 to DM with Kruskal-Wallis Test

[HIV-Reservoir by CCR5/DM Tropism]

Conclusions: In ART-treated adults, the vast majority of persistently infected CD4+ T-cells are memory cells. By contrast, we found that a significant proportion of the reservoir resides in the naïve CD4+ T-cells among Ugandan HIV+ ART-treated children. Infection with DM virus was associated with preferential naïve T-cell infection. In developing strategies to eradicate HIV, it will be important to take into account the high levels of naïve T-cell infection in children, particularly among those with DM virus.

2011, ROME, ITALY


Achan J, Ikilezi G, Kakuru A, Young SL, Havlir DV, Kamya MR, Charlebois ED, Ruel T. HIV-infected Ugandan children suffer high rates of malnutrition and minimal recovery following the initiation of antiretroviral therapy. IAS, Rome, Italy; 15th - 16th July 2011

 

Background: HIV-infected children in Africa suffer high rates of wasting and stunting, but there are limited longitudinal data about what factors lead to improvements in growth. We sought to chacterize the extent of growth recovery that followed the intiation of ART in a cohort of rural Ugandan HIV-infected children.

 

Methods: Subjects were HIV-infected children from an ongoing clinical study in Tororo, Uganda that were either ART-suppressed (HIV RNA < 400 copies/ml) on first line therapy or ART-naive and initiating ART per WHO guidelines. Weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) Z-scores were calculated monthly; CD4 count and percentage, HIV RNA and hemoglobin levels were obtained every 12 weeks. A measure of socioeconomic status (SES) was generated using principal components analysis of household assets. Associations between WAZ, HAZ or WHZ and enrollment age, CD4 count and percentage, hemoglobin, HIV RNA level (log(copies/ml), and SES were analyzed using multivariate logitistic regression. Predictors of individual growth rates (Z-score change per month) were evaluated using multivariate linear regression modelling. Predictors of growth recovery among children who were underweight (WAZ<-2), stunted (HAZ<-2) and wasted (WHZ<-2) to Z-scores > -2 after 12 months of therapy were characterized using Kaplan-Meier survival plots and Cox proportional hazard modelling.

 

Results: ART-naive children (n=110) had similar ages (median 3.1 vs 2.9, p=0.2) but lower CD4 percentage (median 16 vs 30, p<0.001) and CD4 count (median 548 vs 1275, p<0.001) compared to ART-suppressed children (n=56, median duration of prior ART 568 days, IQR:197,670). Greater portions of ART-naive children were underweight (38% vs 20%, p=0.02), stunted (63% vs 45%, p=0.03), and wasted (11% vs 2%, p=0.11). Among ART-naive children, older age (odds ratio, OR:0.014 for age >4 yrs vs < 2yrs, p=0.01) and lower WHO stage (1 or 2 vs 3 or 4, OR:0.08, p=0.003) were associated with reduced odds of wasting at enrollment, but only HIV RNA level was associated with significantly altered risk of stunting (OR 2.2 per log(copies/ml), p =0.004). The majority of ART-naive children demonstrated growth recovery after initiating ART as indicated by increasing Z-scores for WAZ (58%), HAZ(69%), and WHZ(51%). However, after 12 months of therapy, recovery among the severly malnourished from below to above a Z-score of -2 was seen in only 4 of 42 underweight, 3 of 69 stunted, 1 of 11 wasted children. In univariate analysis, severely wasted children with baseline CD4% of at least 25 had shorter median time to recovery (p=0.02) compared to children with CD4%< 25.

 

Conclusions: In this rural cohort of HIV-infected African children, high rates of malnutrition persisted after the intiation of ART. After 12 months, less than 10% of the underweight, stunted, or wasted had recovered to above Z-scores of -2. Notably, WAZ worsened in 42% of children and HAZ worsened in 31% of children. Further study to identify predictors of growth recovery and interventions to complement ART is needed to optimize health outcomes in HIV-infected African children.

2008, MEXICO CITY, MEXICO


Charlebois ED, Ruel T, Cao H, Gasasira A, Achan J, Kateera F, Akello C, Dorsey G, Wong J, Rosenthal P, Kamya M, Havlir D. Risk of short-term progression in Ugandan children not yet eligible for antiretroviral therapy (ART). XVII International AIDS Conference, August 03-08, 2008, Mexico City.


Gasasira A, Ruel T, Charlebois E, Achan A, Akello C, Kateera F, Rosenthal P, Dorsey G, Kamya M, Havlir D. Burden of significant bacterial infections in HIV-infected Ugandan children receiving trimethoprim-sulfamethoxazole prophylaxis. XVII International AIDS Conference, August 03-08, 2008, Mexico City.


Achan J, Ruel T, Kateera F, Kalyango J, Akello C, Gasasira A, Charlebois E, Dorsey G, Rosenthal P, Kekitiinwa A, Havlir D, Kamya M. Reconstitution Inflammatory Syndrome in the first 6 months of antiretroviral therapy in HIV-infected Ugandan children. XVII International AIDS Conference, August 03-08, 2008, Mexico City.

 

T. Ruel, J. Achan, E. Charlebois, D. Havli1, M. Kamya.Sustained viremia is common among HIV-infected Ugandan children receiving antiretroviral therapy (ART) and not detected by WHO CD4 criteria for treatment failure

Background: Without access to HIV RNA testing, practitioners must determine treatment outcomes based on CD4 and clinical criteria alone. We sought to determine how often children experienced sustained viremia (>=2 sequential visits with detectable HIV RNA) beyond 24 weeks of therapy and whether they met WHO CD4 criteria for treatment failure (TF).

 

Methods: Retrospective analysis of data from the Children with HIV and Malaria Project, an observational cohort of 300 ART-naïve HIV-infected Ugandan children. CD4 and HIV RNA were obtained every 12 weeks and ART was initiated per WHO/Ugandan guidelines. All children with at least 2 assessments starting at 6-9 months of ART with simultaneous CD4 count, CD4% and plasma HIV RNA (level of detection 400 copies/ml) were included. TF was defined per WHO 2008 guidelines as new CD4 measures below age-specific thresholds on 2 sequential visits beyond 24 weeks of ART.

 

Results: A total of 117 children with median (range) age of 4.8 (1.2-11.5) years at ART initiation with 7(2-14) visits over 576 (85-1019) days follow-up time were included. 20 (17%) children experienced sustained viremia beyond 24 weeks of ART. Median (range) of first detectable HIV RNA was 41,938 (1,235-405,636) copies/ml. Of these children, 11 maintained viremia at all visits, 5 had initially undetectable HIV RNA but later rebounded and 4 experienced 1-3 undetectable HIV RNA values at a later visits. Of these, only 1 child met criteria for TF child; this child was viremic throughout the follow-up period.

 

Conclusions: In this closely monitored cohort, viral suppression rates were high (83%), but 19 of the 20 children with sustained viremia beyond 24 weeks of ART were not detected using strict WHO CD4 criteria for TF. Virologic monitoring is needed in this setting to alert practitioners to the need for adherence counseling and prevent the development of ART resistance.

 

2006, Toronto, Canada

E.D. Charlebois, MPH, PhD1, P. Srikantiah, MD, MPH1, R. Lin, MD1, M. Walusimbi, MBChB2, A. Okwera, MBChB, MSc2, H. Luzze, MBChB2, C.C. Whalen, MD3, W.H. Boom, MD3, D.V. Havlir, MD1. Factors Influencing Acceptability of Family-Based HIV Counseling and Testing for Tuberculosis Evaluation Subjects in Uganda. The XV International AIDS Conference, Toronto, Canada 2006, Abs# THPE0735

 

2005, Rio de Janeiro, Brazil

Moses R Kamya, Gasasira A, Yeka A, Bakyaita N, Nsobya SL, Francis D, Rosenthal PJ, Dorsey G, Havlir D. “The effect of HIV on malaria treatment outcome among adults and children with uncomplicated falciparum malaria in Uganda,” abstract TuPe1.4C13, 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil, July 2005.