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issn:0269-937
1.  HIV-1 Vpr activates the DNA damage response in renal tubule epithelial cells 
AIDS (London, England)  2009;23(15):2054-2056.
Summary
HIV associated nephropathy (HIVAN) is a major cause of HIV related morbidity and mortality. Pathogenesis involves direct infection of the glomerular and tubular epithelial cells leading to characteristic pathology. Recently, we have shown that HIV-1 Vpr causes hypertrophy, hyperploidy, and apoptosis. Here we report that Vpr activates the DNA damage response resulting in the observed renal phenotype. Renal sections from the HIVAN transgenic mouse model and human biopsies both show an abundant DNA damage response.
doi:10.1097/QAD.0b013e32833088a0
PMCID: PMC3982604  PMID: 19657269
HIV Associated Nephropathy; Vpr; DNA Damage; gamma H2AX; Renal Epithelial Cell
3.  HIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes 
AIDS (London, England)  2013;27(6):10.1097/QAD.0b013e32835e1616.
Objective
To define the relative frequencies of different mechanisms of viral escape.
Design
A population-based approach to examine the distribution of HIV polymorphism associated with diverse population human leucocyte antigens (HLAs) at sites within and flanking CD8 T-cell epitopes as a correlate of likely mechanisms of viral escape.
Methods
Sequence windows surrounding 874 HLA allele-specific polymorphisms across the full HIV-1 proteomic consensus sequence were scanned by an epitope-prediction programme. Either already known or probable CD8 T-cell epitopes with HLA restriction matching that of the proximal HLA association were identified and synthesized. These peptides were used as stimulating antigens in automated enzyme-linked immunospot (ELISpot) assays. Peptide arrays were customized to each individual based on their HLA genotype.
Results
Among HLA-associated HIV polymorphisms detected in the viral sequences of a cohort of 800 individuals with chronic subtype B HIV infection, those which were likely to affect HLA peptide binding were significantly more common than polymorphisms at nonanchor HLA binding sites. HIV epitopes with such polymorphisms were associated with reduced IFNγ responses in ELISpot assays. HIV escape at sites affecting T-cell receptor (TCR) engagement and epitope processing were also evident.
Conclusion
HIV escape from HLA-peptide binding predominates as an effective viral evasion strategy and therefore has implications for inclusion of HLA-adapted epitopes in vaccine immunogens.
doi:10.1097/QAD.0b013e32835e1616
PMCID: PMC3818524  PMID: 23276808
CD8; epitope; escape mutation; HIV-1; HLA-driven; polymorphism; T-cell immunity
4.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
Objective
To examine if altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
Design
Nested cohort study.
Methods
We studied HIV-infected(HIV+) and HIV-uninfected(HIV−) men in the Multicenter AIDS Cohort Study with noncontrast CT to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus and CVD risk factors (RFs).
Results
Significant findings were limited to adiponectin. HIV+ men (n=493) had lower adiponectin levels than HIV− men (n=250) after adjusting for CVD RFs (p<0.0001), which became non-significant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV+ men, lower adiponectin levels were associated with higher CD4+ T cell counts (p= 0.004), longer duration of antiretroviral therapy (p= 0.006) and undetectable HIV RNA levels (p = 0.04) after adjusting for age, race and CVD RFs; only CD4+ cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis > 50% (p <0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV+ and of mixed plaque in HIV− men.
Conclusions
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
doi:10.1097/QAD.0000000000000186
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
5.  Weight and Lean Body Mass Change with Antiretroviral Initiation and Impact on Bone Mineral Density: AIDS Clinical Trials Group Study A5224s 
AIDS (London, England)  2013;27(13):2069-2079.
Objective
To compare the effect initiating different antiretroviral therapy (ART) regimens have on weight, body mass index (BMI), and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD).
Methods
A5224s was a substudy of A5202, a prospective trial of 1857 ART-naïve participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). All subjects underwent dual-energy absorptiometry (DXA) and abdominal CT for body composition. Analyses used 2-sample t-tests and linear regression.
Results
A5224s included 269 subjects: 85% male, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 233 cells/µL. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks post randomization (all p<0.001). Assignment to ATV/r (vs EFV) resulted in significantly greater weight (mean difference 3.35 kg) and BMI gain (0.88 kg/m2; both p=0.02), but not LBM (0.67 kg; p=0.15), while ABC/3TC and TDF/FTC were not significantly different (p≥0.10). In multivariable analysis, only lower baseline CD4 count and higher HIV-1 RNA were associated with greater increase in weight, BMI, or LBM. In multivariable analyses, increased LBM was associated with an increased hip BMD.
Conclusions
ABC/3TC vs. TDF/FTC did not differ in change in weight, BMI, or LBM; ATV/r vs. EFV resulted in greater weight and BMI gain but not LBM. A positive association between increased LBM and increased hip BMD should be further investigated through prospective interventional studies to verify the impact of increased LBM on hip BMD.
doi:10.1097/QAD.0b013e328361d25d
PMCID: PMC3966569  PMID: 24384588
antiretroviral therapy; HIV; body composition; body weight; lean body mass; bone mineral density; randomized clinical trial
6.  Sexual behaviour in a rural high HIV prevalence South African community: time trends in the antiretroviral treatment era 
AIDS (London, England)  2013;27(15):2461-2470.
Objectives
Data from generalized epidemic settings have consistently found that patients on antiretroviral therapy (ART) reduce sexual risk behaviours, but how sexual behaviour changes in the general population in response to ART availability, including amongst HIV-uninfected and undiagnosed adults, has not been characterized in these settings.
Design
General population open cohort.
Methods
We report trends in sexual behaviour indicators for men aged 17–54 years and women aged 17–49 years in rural KwaZulu-Natal province, based on annual sexual behaviour surveys during ART scale-up from 2005 to 2011. Estimates are adjusted for survey non-participation and non-response to individual survey items using inverse probability weighting and multiple imputation. Trends are presented by HIV status, knowledge of status, age and marital status.
Results
Reports of condom use at last sex with a regular partner increased by 2.6% points per year [95% confidence interval (CI) 1.5%, 3.7%] for men and 4.1% per year (3.0%, 5.3%) for women. Condom use at last sex with a casual partner was high and did not change significantly over the period for both sexes. There were statistically significant declines in the percentage reporting multiple partnerships in the last year and the point prevalence of concurrency. Trends within subgroups are generally consistent with overall estimates.
Conclusion
We find no evidence of increased sexual risk-taking following ART availability and protective changes in some behaviours, suggesting that general trends in sexual behaviour are not counter-acting preventive effects of HIV treatment. Continued monitoring of population-level sexual behaviour indicators will be essential to interpret the success of combination-prevention programmes.
doi:10.1097/01.aids.0000432473.69250.19
PMCID: PMC3773237  PMID: 23842132
Africa; antiretroviral therapy; HIV; sexual behaviour; trends
7.  Severe food insecurity is associated with elevated unprotected sex among HIV-seropositive injection drug users independent of HAART use 
AIDS (London, England)  2011;25(16):2037-2042.
Objective
Despite emerging evidence of a significant adverse relationship between food insecurity and sexual risk-taking, data have been primarily derived from resource-constrained settings and HIV-negative populations. To our knowledge, this study is the first to longitudinally evaluate the relationship between food insecurity and unprotected sex among HIV-seropositive people who inject drugs [injection drug users (IDUs)] both on and not on HAART.
Design
Longitudinal analyses were restricted to HIV-positive IDUs who completed baseline and at least one follow-up visit in a prospective cohort (AIDS Care Cohort to evaluate Exposure to Survival Services, 2005–2009).
Methods
We constructed a multivariate logistic model using generalized estimating equations (GEEs) to assess an independent relationship between severe food insecurity (e.g., hunger due to lack of access or means to acquire food) and unprotected vaginal/anal sex.
Results
Among 470 HIV-positive IDUs, the median age was 42 years (interquartile range 36–47) with 61% men and 39% women. The prevalence of severe food insecurity was 71%, with no differences by HAART use. Severe food insecure IDUs were marginally less likely to have a suppressed HIV-1 RNA viral load (31 vs. 39%, p=0.099). In multivariate GEE analyses, severe food insecurity [adjusted odds ratio=2.68, 95% confidence interval 1.49–4.82] remained independently correlated with unprotected sex among HIV-positive IDUs, controlling for age, sex/gender, married/cohabitating partner, binge drug use, homelessness, and HAART use.
Conclusion
These findings highlight a crucial need for structural HIV interventions that incorporate targeted food assistance strategies for IDUs. Given recent evidence of poor virological response among food insecure individuals on HAART, innovative HIV care models should integrate targeted food security programs and early access to HAART.
doi:10.1097/QAD.0b013e32834b35c9
PMCID: PMC3956106  PMID: 21811140
food insecurity; HAART; HIV/AIDS; injection drug use; sexual risk
8.  Social and structural factors associated with HIV disease progression among illicit drug users: A systematic review 
AIDS (London, England)  2012;26(9):1049-1063.
Objective
To systematically review factors associated with HIV disease progression among illicit drug users, focusing on exposures exogenous to individuals that likely shape access and adherence to HIV treatment.
Design
A systematic review of peer-reviewed English-language studies among HIV-seropositive illicit drug users with at least one of these endpoint of interest: a diagnosis of AIDS; death; changes/differences in CD4 cell counts; or changes/differences in plasma HIV-1 RNA levels.
Methods
Articles were included if they reported factors associated with an outcome of interest among a group of illicit drug users. Studies were identified, screened and selected using systematic methods.
Results
Of 2,668 studies matching the search criteria, 58 (2%) met the inclusion criteria, all but one from North America or Western Europe. Overall, 41 (71%) studies contained significant individual-level clinical characteristics or behaviours (e.g., illicit drug use) associated with disease progression. Fifteen studies (26%) identified significant social, physical, economic or policy-level exposures, including incarceration, housing status or lack of legal income.
Conclusion
While past studies demonstrate important environmental exposures that appear to shape access to care and subsequent disease progression, the limited literature to examine these factors demonstrates the need for future research to consider risk environment characteristics and the role they may play in shaping health outcomes from HIV infection among drug users through determining access and adherence to evidence-based care. (198 words)
doi:10.1097/QAD.0b013e32835221cc
PMCID: PMC3955099  PMID: 22333747
Antiretroviral therapy; CD4; drug users; pathogenesis; progression; risk factors; viral load
10.  Putting risk compensation to rest: Reframing the relationship between risk behavior and antiretroviral therapy among injection drug users 
AIDS (London, England)  2012;26(18):2405-2407.
doi:10.1097/QAD.0b013e3283519b42
PMCID: PMC3954705  PMID: 23151496
HAART; HIV; injection drug use; risk behavior; risk compensation
11.  Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach 
AIDS (London, England)  2013;27(9):1473-1481.
Objective
CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown.
Design
A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow-up in relation to AIDS progression.
Methods
Percentages of CD4 and CD8 T cells with HLA-DR± and CD38± were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR± and CD38±) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership.
Results
Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8+CD38– DR– (average = 41% of total CD8 T-cell pool), CD4+CD38– DR– (average = 53% of total CD4 T-cell pool), and CD8+CD38– DR+ (28%); Cluster 2: higher CD8+CD38+DR– (44%) and CD4+CD38+DR– (58%); Cluster 3: higher CD8+CD38+DR+ (49%) and CD4+ CD38+DR– (48%); Cluster 4: higher CD8+CD38+DR+ (49%), CD4+CD38+DR+ (36%) and CD4+CD38– DR+ (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio = 2.13; 95% confidence interval = 1.30–3.50) adjusted for CD4 cell count, HIV RNA, and other confounders.
Conclusion
A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression.
doi:10.1097/QAD.0b013e3283601bad
PMCID: PMC3949252  PMID: 23945505
AIDS; cluster analysis; immune activation
12.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
13.  Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine 
AIDS (London, England)  2012;26(16):2097-2106.
Objective
CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
Design
The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
Methods
Five putative functional polymorphisms were tested for associations with virologic suppression within one year after NNRTI initiation in women naïve to antiretroviral agents (n=91). Principal components (PCs) were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
Results
Rs3745274 was significantly associated with virologic suppression (OR=3.61, 95% CI 1.16-11.22, p trend=0.03); the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66-infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for PCs (p trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
Conclusion
The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted given the potential clinical importance of this finding.
doi:10.1097/QAD.0b013e3283593602
PMCID: PMC3940150  PMID: 22951632
CYP2B6; population substructure; women; NNRTIs; confounding
14.  Antiretroviral treatment changes in adults from Côte d'Ivoire: the roles of tuberculosis and pregnancy 
AIDS (London, England)  2010;24(1):93-99.
Objective
To determine the rates and causes of first antiretroviral treatment (ART) changes in HIV-infected adults in Côte d'Ivoire.
Methods
We evaluated adults who initiated ART in an outpatient clinic in Abidjan. We recorded baseline and follow-up data, including drug prescriptions and reasons for changing to alternative first-line regimens (drug substitution for any reason but failure) or second-line regimens (switch for failure).
Results
2012 HIV-infected adults (73% women) initiated ART. At baseline, 9% of all patients were on treatment for tuberculosis and 3% of women were pregnant. First-line ART consisted of 2 NRTIs (58% stavudine-lamivudine, 42% zidovudine-lamivudine) and efavirenz (63%), nevirapine (32%) or indinavir (5%). Median follow-up time was 16.9 months. During this time, 205 (10%) patients died and 261 (13%) were lost to follow-up. Overall, the rate of treatment modifications was 20.7/100 patient-years (PY). The most common modifications were drug substitutions for intolerance (12.4/100PY), pregnancy (4.5/100PY) and tuberculosis (2.5/100PY). The rates of intolerance-related substitutions were 17.9/100PY for stavudine, 6.3/100PY for nevirapine, 3.9/100PY for zidovudine and 0.1/100PY for efavirenz. Twenty percent of efavirenz substitutions resulted from pregnancy and 18% of nevirapine substitutions were related to tuberculosis treatment.
Conclusions
During the first months following ART initiation, a third of all treatment changes occurred for reasons other than intolerance to the drug or treatment failure. In Africa, drug forecasting is crucial to ensuring the success of HIV treatment programs. Drugs that do not require interruptions during pregnancy or tuberculosis treatment should be made more readily available as first-line drugs in sub-Saharan Africa.
doi:10.1097/QAD.0b013e32832ec1c3
PMCID: PMC3936254  PMID: 19935382
adults; sub-Saharan Africa; antiretroviral treatment; modification; tolerance; pregnancy; tuberculosis; efavirenz; nevirapine
15.  The accuracy of women’s reports of their partner’s male circumcision status in Rakai, Uganda 
AIDS (London, England)  2013;27(4):662-664.
We assessed whether women had accurate knowledge of their partners’ male circumcision (MC) status using survey data (2010–2011) from Rakai, Uganda, and examined characteristics of women who misreported MC status. Among couples in which men were uncircumcised (N=1744), 8.2% women misreported; and among couples where men were confirmed circumcised (N=759), 1.2% women misreported. Younger women were 2.2 times more likely to misreport compared to older women. Misreporting was not associated with other sociodemographics or behavioral characteristics. If women are to act as advocates for MC acceptance, there is a need to educate women, particularly younger women about the nature and recognition of MC.
doi:10.1097/QAD.0b013e32835c557c
PMCID: PMC3932992  PMID: 23169325
Female misreporting; male circumcision scale-up; women group
16.  Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection 
AIDS (London, England)  2011;25(11):1405-1414.
Background
Unintentional loss of weight and muscle due to aging and disease has been associated with increased mortality. Wasting and weight loss occur in HIV infection even in the modern era of effective antiretroviral therapy.
Methods
We determined the association of MRI-measured regional and total skeletal muscle and adipose tissue with 5-year, all-cause mortality in 922 HIV-infected persons in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
Results
After 5 years of follow-up, HIV-infected participants with arm skeletal muscle in the lowest tertile had a mortality rate of 23%, compared with 11 and 8% for those in the middle and highest tertiles. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, inflammatory markers, and renal disease, we found that lower arm skeletal muscle, lower leg skeletal muscle and higher visceral adipose tissue (VAT) were each independently associated with increased mortality. Those in the lowest tertile of arm or leg skeletal muscle had higher odds of death [arm: odds ratio (OR)=2.0, 95% confidence interval (CI) 0.96–4.0; leg: OR=2.4, 95% CI 1.2–4.8] compared with the highest respective tertiles. Those in the highest tertile of VAT had 2.1-fold higher odds of death (95% CI 1.1–4.0) compared with the lowest VAT tertile.
Conclusion
Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on body mass index in clinical practice.
doi:10.1097/QAD.0b013e32834884e6
PMCID: PMC3933309  PMID: 21572308
body composition; cachexia; fat redistribution; HIV infection; lipoatrophy; lipodystrophy; mortality; sarcopenia
17.  Contraceptive method and pregnancy incidence among African women in HIV-1 serodiscordant partnerships 
AIDS (London, England)  2012;26(4):513-518.
Background
Effective contraception reduces unintended pregnancies and is a central strategy to reduce vertical HIV-1 transmission for HIV-1 infected women.
Methods
Among 2269 HIV-1 seropositive and 1085 seronegative women from 7 African countries who were members of HIV-1 serodiscordant heterosexual partnerships and who were participating in an HIV-1 prevention clinical trial, we assessed pregnancy incidence for women using various contraceptive methods using multivariate Andersen-Gill analysis.
Results
Compared with women using no contraceptive method, pregnancy incidence was significantly reduced among HIV-1 seropositive and seronegative women using injectable contraception (adjusted hazard ratio (aHR) 0.24, p=0.001 and aHR 0.25, p<0.001, respectively). Oral contraceptives significantly reduced pregnancy risk only among HIV-1 seropositive women (aHR 0.51, p=0.004) but not seronegative women (aHR 0.64, p=0.3), and, for both seropositive and seronegative women, oral contraceptive pill users were more likely to become pregnant than injectable contraceptive users (aHR 2.22, p=0.01 for HIV-1 seropositive women and aHR 2.65, p=0.09 for HIV-1 seronegative women). Condoms, when reported as being used as the primary contraceptive method, marginally reduced pregnancy incidence (aHR 0.85, p=0.1 for seropositive women and aHR 0.67, p=0.02 for seronegative women). There were no pregnancies among women using intrauterine devices, implantable methods or who had undergone surgical sterilization, although these methods were used relatively infrequently.
Conclusions
Family planning programs and HIV-1 prevention trials need innovative ways to motivate uptake and sustained use of longer acting, less user-dependent contraception for women who do not desire pregnancy.
doi:10.1097/QAD.0b013e32834f981c
PMCID: PMC3932300  PMID: 22156966
HIV-1; serodiscordant couples; contraception; Africa; women
19.  Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression 
AIDS (London, England)  2013;27(4):507-518.
Objective(s)
There is limited information on full-length genome sequences and the early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of viruses spread in Africa. The purpose of this study was to characterize the earliest changes across the genome of subtype C viruses following transmission, to better understand early control of viremia.
Design
We derived the near full-length genome sequence responsible for clinical infection from five HIV subtype C-infected individuals with different disease progression profiles and tracked adaption to immune responses in the first six months of infection.
Methods
Near full-length genomes were generated by single genome amplification and direct sequencing. Sequences were analyzed for amino acid mutations associated with cytotoxic T-lymphocyte (CTL) or antibody (Ab)-mediated immune pressure, and for reversion.
Results
Fifty-five sequence changes associated with adaptation to the new host were identified with 38% attributed to CTL pressure; 35% to antibody pressure; 16% to reversions and the remainder were unclassified. Mutations in CTL epitopes were most frequent in the first 5 weeks of infection, with the frequency declining over time with the decline in viral load. CTL escape predominantly occurred in nef, followed by pol and env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes with only 7% reaching fixation within the six month period.
Conclusions
There was rapid virus adaptation following transmission, predominantly driven by CTL pressure, with most changes occurring during high viremia. Rapid escape and complex escape pathways provide further challenges for vaccine protection.
doi:10.1097/QAD.0b013e32835cab64
PMCID: PMC3720865  PMID: 23370465
HIV-1; Africa; genome; acute infection; cytotoxic T-lymphocytes; progression
20.  Safety and efficacy of topical Cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women 
AIDS (London, England)  2013;27(4):545-551.
Objective
To evaluate the safety and efficacy of topical cidofovir for treatment of high-grade squamous perianal and vulvar intraepithelial neoplasia (PAIN and VIN) lesions in HIV-positive individuals.
Design
Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium (AMC)
Methods
HIV-positive patients with biopsy-proven high-grade PAIN that was ≥ 3 cm2 were enrolled. PAIN biopsy specimens were assessed for HPV using PCR and type-specific HPV probing. Subjects applied 1% topical cidofovir to PAIN and VIN (if present) for 6 two-week cycles. Results were designated as complete response (CR), partial response (PR) (> 50% reduction in size), stable disease (SD), or progressive disease (PD).
Results
Twenty-four men and 9 women (8 with high-grade VIN as well) were enrolled. Mean age was 44 years, mean CD4+ count was 412 cells/μl. HPV DNA (most commonly HPV16) was detected in all pre-treatment study specimens. Twenty six (79%) subjects completed treatment per protocol—CR: 5 (15%); PR: 12 (36%), SD: 7 (21%); PD: 2 (6%) (1 with a superficially invasive cancer and 1 with new area of high-grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/burning/irritation (25 subjects) and ulceration (13 subjects).
Conclusions
Topical cidofovir had 51% efficacy in the short-term treatment of high-grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed.
doi:10.1097/QAD.0b013e32835a9b16
PMCID: PMC3759510  PMID: 23032420
Perianal intraepithelial neoplasia; Vulvar intraepithelial neoplasia; cidofovir; HIV; HPV; Bowen’s disease
22.  Polymorphic LEDGF/p75 variants support efficient HIV-1 infection ex vivo 
AIDS (London, England)  2013;27(4):10.1097/QAD.0b013e32835af34c.
doi:10.1097/QAD.0b013e32835af34c
PMCID: PMC3856184  PMID: 23364444
23.  High HIV-1 incidence, correlates of HIV-1 acquisition, and high viral loads following seroconversion among men who have sex with men in Coastal Kenya 
AIDS (London, England)  2013;27(3):437-446.
Background
HIV-1 incidence estimates and correlates of HIV-1 acquisition in African men who have sex with men are largely unknown.
Methods
Since 2005, HIV-1-uninfected men who reported sex with men and women (MSMW) or sex with men exclusively (MSME) were followed at scheduled visits for collection of behavioural and clinical examination data and plasma for HIV-1 testing. Urethral or rectal secretions were collected from symptomatic men to screen for gonorrhoea. Poisson regression methods were used to estimate adjusted incidence rate ratios (aIRR) to explore associations between risk factors and incident HIV-1 infection. Plasma viral loads (PVL) were assessed over two years following seroconversion.
Results
Overall HIV-1 incidence in 449 men was 8.6 (95% confidence interval [CI]: 6.7–11.0) per 100 person-years (py). Incidence was 5.8 (95% CI: 4.2–7.9) per 100 py among MSMW, and 35.2 (95% CI: 23.8–52.1) per 100 py among MSME. Unprotected sex, receptive anal intercourse, exclusive sex with men, group sex, and gonorrhoea in the past 6 months were strongly associated with HIV-1 acquisition, adjusted for confounders. PVL in seroconverters was >4 log10 copies/mL at 230 (73.4%) of 313 visits in MSMW and 153 (75.0%) of 204 visits in MSME.
Conclusions
HIV-1 incidence is very high among MSM in coastal Kenya, and many seroconverters maintain high PVL for up to two years after infection. Effective HIV-1 prevention interventions, including treatment as prevention, are urgently needed in this population.
doi:10.1097/QAD.0b013e32835b0f81
PMCID: PMC3929859  PMID: 23079811
HIV-1 incidence; MSM; gonorrhoea; anal intercourse; viral load; sexually transmitted infection; group sex; Africa
24.  Impact of the HIV epidemic on population and household structure: the dynamics and evidence to date 
AIDS (London, England)  2004;18(0 2):S45-S53.
Background
HIV is contracted most frequently at birth and during early adulthood. The epidemic may thus impact the demographic structure and the household structure of affected populations.
Methods
This paper reviews earlier evidence of such an impact, uses demographic theory to anticipate its changes over time, and reviews the most recent evidence for indications of these changes.
Results
Modest increases in the male : female ratio are beginning to show within certain age groups only (approximately 15% among 25–34 year olds). Similarly sized increases in the proportion of 15–29 year olds relative to 30–54 year olds are observed in some age pyramids. These ‘youth bulges’ are expected to fade out, whereas an aging effect phases in with the fertility impact of the epidemic. In the longer run, the size of all age groups will be reduced, but relatively less so for middle-aged adults. Proportions of orphans and widows have increased in the most affected countries. Fewer remarriage probabilities for widows were observed. Resulting increases in the proportion of female-headed households should only be temporary, as female mortality is catching up with male mortality. The number of double orphans is beginning to increase, but overall, orphans continue to live predominantly with a family member, most often the grandparents if not with the surviving parent.
Conclusion
To date, the epidemic’s impact on the population and household structure has been limited by demographic (aging) and social (adaptive movements of kin across households) processes that contribute to diffuse the epidemic throughout the entire population and all households.
PMCID: PMC3929185  PMID: 15319743
sex ratio; age structure; household structure; widows; orphans
25.  CD4 eligibility thresholds: an analysis of the time to antiretroviral treatment in West African HIV-1 seroconverters 
AIDS (London, England)  2011;25(6):819-823.
Background
WHO recommends initiating combination antiretroviral treatment (ART) at the minimal threshold of 350 CD4 cells/mm3. In sub-Saharan Africa, the time for a recently infected patient to reach this threshold is unclear.
Method
We estimated the probability of reaching different CD4 thresholds over time in the ANRS 1220 cohort of HIV-1 seroconverters in Côte d’Ivoire. CD4 slopes were estimated using a mixed linear model. Probabilities of crossing the 350 and 500 CD4 cells/mm3 thresholds were estimated by the Kaplan-Meier method.
Results
Between 1997 and 2009, 304 recent seroconverters have been enrolled in the Primo-CI cohort (62% men, median baseline age 29 years, median time since the estimated date of seroconversion 9 months). The probability of having a first CD4 count below 500/mm3 was 0.57, 0.72, 0.79 and 0.84 at study entry, 2, 4 and 6 years, respectively. For a first CD4 count below 350/mm3, these figures were 0.29, 0.40, 0.55 and 0.67. The time for 75% of patients to reach the threshold was 3.0 years for 500 CD4/mm3 and 7.0 years for 350 CD4/mm3.
Conclusion
Almost one third of recent seroconverters had a CD4 count below the current ART eligibility threshold at first contact, about 6% more crossed it each subsequent year, and 25% remained above this threshold after 7 years. If the threshold was raised to 500 cells/mm3, 57% of recent seroconverters would immediately be eligible, while 14% would remain above the threshold at 7 years. These results should help modelers and treatment providers anticipate the need in antiretroviral drugs.
doi:10.1097/QAD.0b013e32834625d3
PMCID: PMC3921664  PMID: 21412060

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