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1.  HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression 
Background. Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown.
Methods. HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC.
Results. In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4+ T-cell count <250 cells/mm3, antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9–11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC ≤67% was not significantly different (HR, 2.2; 95% CI, 1.0–4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC.
Conclusions. HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms.
PMCID: PMC3864385  PMID: 23922373
HIV-1 Subtype; subtype A; subtype D; disease progression; polymerase; replication capacity; amino acid polymorphisms
2.  Alterations in Cardiac and Pulmonary Function in Pediatric Rapid Human Immunodeficiency Virus Type 1 Disease Progressors 
Pediatrics  2000;105(1):e9.
Infants with human immunodeficiency virus type 1 (HIV-1) can be divided into rapid progressors (RPs) and non-rapid progressors (non-RPs) based on symptoms and immunologic status, but detailed information about cardiac and pulmonary function in RP and non-RP children needs to be adequately described.
Cardiac, pulmonary, and immunologic data and HIV-1 RNA burden were periodically measured in 3 groups: group I, 205 vertically infected children enrolled from 1990 to 1994 and followed through 1996; group II, a prospectively studied cohort enrolled at birth that included 93 infected (group IIa); and 463 noninfected infants (group IIb).
Mean respiratory rates were generally higher in group IIa RP than non-RP children throughout the period of follow-up, achieving statistical signifance at 1 month, 12 months, 24 months, 30 months, and 48 months of follow-up. Non-RP and group IIb (HIV-uninfected children) had similar mean respiratory rates from birth to 5 years of age.
Significant differences in mean respiratory rates were found between group I RP and non-RP at 7 age intervals over the first 6 years of life. Mean respiratory rates were higher in RP than in non-RP at <1 year, 2.0 years, 2.5 years, 3.0 years, 3.5 years, 4.0 years, and 6.0 years of age.
Mean heart rates in group IIa RP, non-RP, and group IIb differed at every age. Rapid progressors had higher mean heart rates than non-RP at all ages through 24 months. Mean heart rates at 30 months through 60 months of age were similar for RP and non-RP children. Non-RP children had higher mean heart rates than did group IIb at 8 months, 24 months, 36 months, 42 months, 48 months, 54 months, and 60 months of age.
In group I, RP had higher mean heart rates than non-RP at 2.0 years, 2.5 years, 3.0 years, and 4.0 years of age. After 4 years of age, the non-RP and RP had similar mean heart rates.
Mean fractional shortening differed between the 3 group II subsets (RP, non-RP, and IIb) at 4, 8, 12, 16, and 20 months of age. Although mean fractional shortening was lower in RP than in non-RP in group II at all time points between 1 and 20 months, the mean fractional shortening was significantly lower in RP only at 8 months when restricting the statistical comparisons to the 2 HIV-infected groups (RP and non-RP). Mean fractional shortening increased in the first 8 months of life followed by a gradual decline through 5 years of age among group IIb children. No significant differences among the 3 groups in mean fractional shortening were detected after 20 months of age.
In group I, differences between RP and non-RP in mean fractional shortening were detected at 1.5, 2.0, 2.5, and 3.0 years of age. After 3 years of age, group means for fractional shortening in RP and non-RP did not differ. Because of the limited data from the first months of the group I patients, it could not be determined whether this group experienced the gradual early rise in mean fractional shortening seen in the group II infants.
In group IIa, RP had more clinical (eg, oxygen saturation <96%) and chest radiographic abnormalities (eg, cardiomegaly) at 18 months of life. RP also had significantly higher 5-year cumulative mortality than non-RP, higher HIV-1 viral burdens than non-RP, and lower CD8+ T-cell counts.
Rapid disease progression in HIV-1-infected infants is associated with significant alterations in heart and lung function: increased respiratory rate, increased heart rate, and decreased fractional shortening. The same children exhibited the anticipated significantly increased 5-year cumulative mortality, increased serum HIV-1 RNA load, and decreased CD8+ (cytotoxic) T-cell counts. Measurements of cardiopulmonary function in HIV-1-infected children seem to be useful in the total assessment of HIV-1 disease progression.
PMCID: PMC4331103  PMID: 10617746
3.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
4.  Better Tests, Better Care: Improved Diagnostics for Infectious Diseases 
In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.
PMCID: PMC3820169  PMID: 24200831
diagnostics; rapid diagnostics; point-of-care testing; molecular diagnostics; clinical microbiology; infectious diseases
5.  Pooling Ocular Swab Specimens from Tanzania for testing by Roche Amplicor and Aptima Combo 2 Assays for the detection of Chlamydia trachomatis: Accuracy and Cost Savings 
Ocular swabs collected in Tanzania were evaluated by Amplicor CT and Aptima Combo2 assays for the detection of Chlamydia trachomatis (CT) to determine if pooling could be used to reduce the cost of detection. Pooling would be an accurate method and so far resulted in a cost-savings of 62.2%.
PMCID: PMC4160034  PMID: 24079951
6.  Herpes Simplex Virus Type 2 Infection among Commercial Sex Workers in Kunming, Yunnan Province, China 
International journal of STD & AIDS  2008;19(10):694-697.
A cross-sectional prevalence survey was conducted to determine the sociodemographic correlates of HSV-2 infection among commercial sex workers (CSWs) in Kunming, Yunnan Province of China. HSV-2 prevalence was 33.0%, HIV infection was 2.4%, and HCV infections was 6.8%. Subjects who were positive for HSV-2 had a significantly higher prevalence of HIV infection (5.5% vs. 0.9%, p=0.002; OR: 6.4, p=0.006) and HCV infection (18.7% vs. 2.4%, p<0.001; OR: 7.6, p<0.001) compared to HSV-2 negative individuals. Risk factors that increased the odds of HSV-2 infection were HIV infection, HCV infection, being female, and having a steady sex partner within the last six months (p≤0.01). In a multivariate analysis, female sex workers (OR: 6.6, p<0.001), HCV infection (OR: 5.9, p<0.001), and having a sex partner within the last 6 months (OR: 2.2, p<0.05) had greater odds of being infected with HSV-2. A strong relationship was found between HSV-2, HIV, and HCV infections.
PMCID: PMC3991299  PMID: 18824623
commercial sex workers (CSWs); herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); hepatitis C virus (HCV); China
7.  Reply to Wertheim et al 
The Journal of Infectious Diseases  2013;207(7):1182-1183.
PMCID: PMC3611769  PMID: 23315325
8.  HIV Diversity as a Biomarker for HIV Incidence Estimation: Including a High-Resolution Melting Diversity Assay in a Multiassay Algorithm 
Journal of Clinical Microbiology  2014;52(1):115-121.
Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data.
PMCID: PMC3911463  PMID: 24153134
9.  Cohort and Age Effects of Mass Drug Administration on Prevalence of Trachoma: A Longitudinal Study in Rural Tanzania 
Mass drug administration (MDA) is part of the SAFE strategy for trachoma elimination. This study examined the effect of three annual MDAs on prevalence of trachoma among 13 longitudinal cohorts of Tanzanian children.
Children younger than 10 years were assigned to cohorts based on age at baseline and followed annually for 3 years, with newborns assigned to new cohorts over time. Annual MDA consisted of topical tetracycline for children younger than 6 months and oral azithromycin for those 6 months and older. Follicular trachoma (TF) and Chlamydia trachomatis infection status were assessed annually before the next MDA. Prevalence and risk factors for TF and infection at each age were compared across cohorts.
At each survey, most age groups and cohorts had MDA coverage of more than 80% and showed decreased TF prevalence after every MDA. One cohort had consistently lower coverage, higher-than-expected TF and infection at ages 6 and 7, and elevated risk of TF at age 7 relative to the preceding cohort in spite of receiving one additional MDA (odds ratio 2.3, 95% confidence interval 1.0–5.2). Cohorts aged 1 or older at baseline generally showed reductions in TF and infection after each MDA, whereas younger cohorts showed decreased infection but increased TF over time. Successive cohorts of never-treated children younger than 1 year showed sequential TF and infection reductions with each MDA (P < 0.001).
Multiple MDAs significantly reduce trachoma prevalence and appear to increasingly protect children born into these communities. The youngest children show declining/stable rates of infection but increasing rates of trachoma, which may reflect longer duration of clinical signs.
In this longitudinal study, three rounds of MDA significantly reduced prevalence of trachoma. Repeat MDAs were associated with progressively lower prevalence among children born into communities that had previously undergone MDA. Lower coverage appeared to be associated with persistent cohort effects.
PMCID: PMC3985515  PMID: 24448262
trachoma; mass drug administration (MDA); Tanzania; cohort study; population-based study
10.  Male circumcision decreases high-risk human papillomavirus viral load in female partners: a randomized trial in Rakai, Uganda 
Male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in female partners. We evaluated the intensity of HR-HPV viral DNA load in HIV-negative, HR-HPV-positive female partners of circumcised and uncircumcised men. HIV-negative men and their female partners were enrolled in randomized trials of MC in Rakai, Uganda. Vaginal swabs were tested for HR-HPV genotypes by Roche HPV Linear Array which provides a semi-quantitative measure of HPV DNA by the intensity of genotype-specific bands (graded:1-4). We assessed the effects of MC on female HR-HPV DNA load by comparing high intensity linear array bands (3-4) to low intensity bands (1-2) using an intention-to-treat analysis. Prevalence risk ratios (PPR) of high intensity bands in partners of intervention versus control arm men were estimated using log-binomial regression with robust variance. The trial included 335 women with male partners in the intervention arm and 340 in the control arm. At enrollment, the frequency of HR-HPV high intensity linear array bands was similar in both study arms. At 24 months follow-up, the prevalence of high intensity bands among women with detectable HRHPV was significantly lower in partners of intervention arm (42.7%) than control arm men (55.1%, PRR= 0.78, 95%CI 0.65-0.94, p=0.02), primarily among incident HR-HPV infections (PRR=0.66, 95% CI 0.50-0.87, p=0.003), but not persistent infections (PRR=1.02, 95% CI 0.83-1.24). Genotypes with high HR-HPV band intensity were more likely to persist (adjHR=1.27 95% CI 1.07-1.50), irrespective of male partner circumcision status. MC reduces HR-HPV DNA load in newly infected female partners.
PMCID: PMC3732529  PMID: 23400966
Human papillomavirus (HPV); male circumcision; Uganda; cervical cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity; HIV
11.  Reactivation of Herpes Simplex Virus Type 2 After Initiation of Antiretroviral Therapy 
The Journal of Infectious Diseases  2013;208(5):839-846.
Background. The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated.
Methods. GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding.
Results. Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04–3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35–1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48–4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04–.41).
Conclusions. The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation.
PMCID: PMC3733512  PMID: 23812240
herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); immune reconstitution inflammatory syndrome (IRIS); acyclovir; reactivation; Uganda
12.  Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial 
Journal of Clinical Microbiology  2014;52(3):844-848.
HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P = 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P < 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.
PMCID: PMC3957790  PMID: 24371237
13.  Behavioral and Biomedical Combination Strategies for HIV Prevention 
Around 2.5 million people become infected with HIV each year. This extraordinary toll on human life and public health worldwide will only be reversed with effective prevention. What’s more, in the next few years, it is likely at least, that no single prevention strategy will be sufficient to contain the spread of the disease. There is a need for combination prevention as there is for combination treatment, including biomedical, behavioral, and structural interventions. Expanded HIV prevention must be grounded in a systematic analysis of the epidemic’s dynamics in local contexts. Although 85% of HIV is transmitted sexually, effective combinations of prevention have been shown for people who inject drugs. Combination prevention should be based on scientifically derived evidence, with input and engagement from local communities that fosters the successful integration of care and treatment.
Each year, 2.5 million people are infected with HIV. Although multiple prevention strategies exist, they must be effective, affordable, and population-specific.
PMCID: PMC3405825  PMID: 22908192
14.  Differential Specificity of HIV Incidence Assays in HIV Subtypes A and D-Infected Individuals from Rakai, Uganda 
AIDS Research and Human Retroviruses  2013;29(8):1146-1150.
Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and for samples where that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D-infected individuals, samples misclassified by one assay were 3.5 times more likely to be misclassified by the other assay. Differential misclassification by infecting subtype of long-term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D cocirculate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D-infected individuals limits the utility of using these assays in combination within this population.
PMCID: PMC3715796  PMID: 23641870
15.  Previously Transmitted HIV-1 Strains Are Preferentially Selected During Subsequent Sexual Transmissions 
The Journal of Infectious Diseases  2012;206(9):1433-1442.
Background. A genetic bottleneck is known to exist for human immunodeficiency virus (HIV) at the point of sexual transmission. However, the nature of this bottleneck and its effect on viral diversity over time is unclear.
Methods. Interhost and intrahost HIV diversity was analyzed in a stable population in Rakai, Uganda, from 1994 to 2002. HIV-1 envelope sequences from both individuals in initially HIV-discordant relationships in which transmission occurred later were examined using Sanger sequencing of bulk polymerase chain reaction (PCR) products (for 22 couples), clonal analysis (for 3), and next-generation deep sequencing (for 9).
Results. Intrahost viral diversity was significantly higher than changes in interhost diversity (P < .01). The majority of HIV-1–discordant couples examined via bulk PCR (16 of 22 couples), clonal analysis (3 of 3), and next-generation deep sequencing (6 of 9) demonstrated that the viral populations present in the newly infected recipient were more closely related to the donor partner's HIV-1 variants found earlier during infection as compared to those circulating near the estimated time of transmission (P = .03).
Conclusions. These findings suggest that sexual transmission constrains viral diversity at the population level, partially because of the preferential transmission of ancestral as opposed to contemporary strains circulating in the transmitting partner. Future successful vaccine strategies may need to target these transmitted ancestral strains.
PMCID: PMC3466994  PMID: 22997233
16.  Prevalence and Factors Associated with Herpes Simplex Virus Type 2 Infection in Patients Attending a Baltimore City Emergency Department 
PLoS ONE  2014;9(7):e102422.
Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED).
An identity unlinked-serosurvey was conducted between 6/2007 and 9/2007 in the JHH ED; sera were tested by the Focus HerpeSelect ELISA. Prevalence risk ratios (PRR) were used to determine factors associated with HSV-2 infection.
Of 3,408 serum samples, 1,853 (54.4%) were seropositive for HSV-2. Females (adjPRR  = 1.47, 95% CI 1.38–1.56), non-Hispanic blacks (adjPRR  = 2.03, 95% CI 1.82–2.27), single (adjPRR  = 1.15, 95% CI 1.07–1.25), divorced (adjPRR  = 1.28, 95% CI 1.15–1.41), and unemployed patients (adjPRR  = 1.13, 95% CI 1.05–1.21) had significantly higher rates of HSV-2 infection. Though certain zip codes had significantly higher seroprevalence of HSV-2, this effect was completely attenuated when controlling for age and gender.
Seroprevalence of HSV-2 in the JHH ED was higher than U.S. national estimates; however, factors associated with HSV-2 infection were similar. The high seroprevalence of HSV-2 in this urban ED highlights the need for targeted testing and treatment. Cross-sectional serosurveys in the urban ED may help to examine the epidemiology of HSV-2.
PMCID: PMC4103852  PMID: 25036862
17.  Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis 
AIDS Research and Human Retroviruses  2013;29(7):1026-1030.
A high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement ≥9.3 kPa (cases=133) and normal controls (n=133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR=1.19, p=0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR=1.54, p<0.001); however, the opposite was observed in HIV-negative individuals (adjMOR=0.57, p=0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease.
PMCID: PMC3685686  PMID: 23548102
18.  Differential loss of invariant NKT cells and FoxP3+ regulatory T cells in HIV-1 subtype A and subtype D infections 
HIV-1 subtype D is associated with faster disease progression as compared to subtype A. Immunological correlates of this difference remain undefined. We investigated invariant natural killer T cells and FoxP3+ regulatory T cells in Ugandans infected with either subtype. Loss of iNKT cells was pronounced in subtype D, whereas Tregs displayed more profound loss in subtype A infection. iNKT cell levels were associated with CD4 T cell IL-2 production in subtype A, but not D, infection. Thus, these viral subtypes are associated with differential loss of iNKT cells and Tregs that may influence the quality of the adaptive immune response.
PMCID: PMC3683089  PMID: 23403863
HIV-1; viral subtype; AIDS; iNKT cell; CD1d; T regulatory cell
19.  Financial Implications of Male Circumcision Scale-Up for the Prevention of HIV and Other Sexually Transmitted Infections in a Sub-Saharan African Community 
Sexually transmitted diseases  2013;40(7):559-568.
The financial implications of male circumcision (MC) scale-up in sub-Saharan Africa associated with reduced HIV have been evaluated. However, no analysis has incorporated reduction in a comprehensive set of other sexually transmitted infections (STIs), including human papillomavirus, herpes simplex virus type 2, genital ulcer disease, bacterial vaginosis and trichomoniasis.
A Markov model tracked a dynamic population undergoing potential MC scale-up, as individuals experienced MC procedures, procedure-related adverse events, MC-reduced STIs, and accrued any associated costs. Rakai, Uganda was used as a prototypical rural sub-Saharan African community. Monte Carlo microsimulations evaluated outcomes under four alternative scale-up strategies to reach 80% MC coverage among men 15-49, in addition to a baseline strategy defined by current MC rates in central Uganda. Financial outcomes included direct medical expenses only, and were evaluated over 5 and 25 years. Costs were discounted to the beginning of each time period, coinciding with the start of MC scale-up, and expressed in US$2012.
Cost savings from infections averted by MC vary from $197,531 after 5 years of a scale-up program focusing on adolescent/adult procedures to over $13 million after 25 years, under a strategy incorporating increased infant MCs. Over a 5-year period, reduction in HIV contributes to 50% of cost savings, and over 25 years, this contribution rises to nearly 90%.
STIs other than HIV contribute to cost savings associated with MC scale-up. Previous analyses, focusing exclusively on the financial impact through averted HIV, may have underestimated true cost savings by 10-50%.
PMCID: PMC3752094  PMID: 23965771
male circumcision; HIV; HPV; sexually transmitted infections; herpes simplex virus type 2 (HSV-2); bacterial vaginosis; trichomoniasis; cost-effectiveness; Markov; Monte Carlo; Africa; Uganda
20.  Frequency and Implications of HIV Superinfection 
The Lancet infectious diseases  2013;13(7):622-628.
HIV superinfection (HIV-SI) occurs when an HIV infected individual is infected with a new distinct HIV viral strain. HIV-SI has been reported throughout the world, and studies have reported HIV-SI incidence rates of 0% to 7.7% per year. Recent use of next-generation sequencing has improved detection of HIV-SI. Several studies have suggested that HIV-SI may occur at rates comparable to initial HIV infection. HIV-SI has been shown to be transmitted by injecting drug use, heterosexual and homosexual intercourse. Clinicians should encourage safe sexual and injecting drug use practices for HIV-infected patients since HIV-SI has detrimental effects on clinical outcomes, and may pose a concern for large scale antiretroviral treatment plans. The occurrence of HIV-SI has implications for vaccine research since it appears natural HIV infection is not fully protective against a subsequent HIV infection. Additional collaborative HIV-SI research is necessary which might benefit patient care and inform future vaccine design.
PMCID: PMC3752600  PMID: 23726798
HIV; HIV-1; superinfection; dual infection; double infection; reinfection; re-infection; antiretroviral; next generation sequencing; HIV pathogenesis; HIV clinical care
21.  A Comparison of Two Measures of HIV Diversity in Multi-Assay Algorithms for HIV Incidence Estimation 
PLoS ONE  2014;9(6):e101043.
Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence.
Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity (the percentage of ambiguous bases in a 1,302 base pair pol region). Samples were classified as MAA positive (likely from individuals with recent HIV infection) if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of cross-sectional incidence estimates for three cohort studies.
The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguity-based MAA. The shadows for both MAAs were <1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion.
MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation.
PMCID: PMC4072769  PMID: 24968135
22.  Human Papillomavirus Clearance Among Males Is Associated With HIV Acquisition and Increased Dendritic Cell Density in the Foreskin 
The Journal of Infectious Diseases  2013;207(11):1713-1722.
Background. The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated.
Methods. A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and controls were 787 males who were persistently negative for HIV. The Roche HPV Linear Array Genotype Test detected high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) genotypes. Generalized estimating equations logistic regression was used to estimate adjusted odds ratios (aORs) of HIV seroconversion. In addition, densities of CD1a+ dendritic cells, CD4+ T cells, and CD8+ T cells were measured using immunohistochemistry analysis in foreskins of 79 males randomly selected from participants in the circumcision trial.
Results. HR-HPV or LR-HPV acquisition was not significantly associated with HIV seroconversion, after adjustment for sexual behaviors. However, HR-HPV and LR-HPV clearance was significantly associated with HIV seroconversion (aOR, 3.25 [95% confidence interval {CI}, 1.11–9.55] and 3.18 [95% CI, 1.14–8.90], respectively). The odds of HIV seroconversion increased with increasing number of HPV genotypes cleared (P < .001, by the test for trend). The median CD1a+ dendritic cell density in the foreskin epidermis was significantly higher among males who cleared HPV (72.0 cells/mm2 [interquartile range {IQR}, 29.4–138.3 cells/mm2]), compared with males who were persistently negative for HPV (32.1 cells/mm2 [IQR, 3.1–96.2 cells/mm2]; P = .047), and increased progressively with the number of HPV genotypes cleared (P = .05).
Conclusions. HPV clearance was associated with subsequent HIV seroconversion and also with increased epidermal dendritic cell density, which potentially mediates HIV seroconversion.
PMCID: PMC3636782  PMID: 23345339
human papillomavirus (HPV); male circumcision; HIV; AIDS; Uganda; penile cancer; cervical cancer; sexually transmitted infections
23.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
24.  HIV Type 1 Genetic Variation in Foreskin and Blood from Subjects in Rakai, Uganda 
The foreskin contains a subset of dendritic cells, macrophages, and CD4+ and CD8+ T cells that may be targets for initial HIV infection in female-to-male sexual transmission of HIV-1. We present analyses comparing HIV-1 sequences isolated from foreskin DNA and serum RNA in 12 heterosexual men enrolled in an adult male circumcision trial performed in Rakai, Uganda. Phylogenetic analysis demonstrated three topologies: (1) little divergence between foreskin and serum, (2) multiple genetic bottlenecks occurring in both foreskin and serum, and (3) complete separation of foreskin and serum populations. The latter tree topology provided evidence that foreskin may serve as a reservoir for distinct HIV-1 strains. Distance and recombination analysis also demonstrated that viral genotypes in the foreskin might segregate independently from the circulating pool of viruses.
PMCID: PMC3380386  PMID: 21902587
25.  Male Circumcision and Mycoplasma genitalium Infection in Female Partners: a Randomized Trial in Rakai, Uganda 
Sexually transmitted infections  2013;90(2):150-154.
Previous randomized trial data have demonstrated that male circumcision reduces Mycoplasma genitalium prevalence in men. We assessed whether male circumcision also reduces M. genitalium infection in female partners of circumcised men.
HIV-negative men were enrolled and randomized to either male circumcision or control. Female partners of male trial participants from the intervention (n=437) and control (n=394) arms provided interview information and self-collected vaginal swabs that were tested for M. genitalium by APTIMA transcription-mediated-amplification-based assay. Prevalence risk ratios (PRR) and 95% confidence intervals (95%CI) of M. genitalium prevalence in intervention versus control group were estimated using Poisson regression. Analysis was by intention-to-treat. An as-treated analysis was conducted to account for study-group crossovers.
Male and female partner enrollment sociodemographic characteristics, sexual behaviors, and symptoms of STIs were similar between study arms. Female M. genitalium prevalence at year-two was 3.2% (14/437) in intervention arm and 3.6% (14/394) in control arm (PRR=0.90, 95%CI 0.43–1.89, p=0.78). In an as-treated analysis, the prevalence of M. genitalium was 3.4% in female partners of circumcised men and 3.3% in female partners of uncircumcised men (PRR= 1.01, 95%CI 0.48–2.12, p=0.97).
Contrary to findings in men, male circumcision did not affect Mycoplasma genitalium infection in female partners.
PMCID: PMC4018720  PMID: 24259189
Male circumcision; mycoplasma genitalium; HIV; Uganda; sexually transmitted infections; transmission

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