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Monitoring human immunodeficiency virus type 1 (HIV-1) drug resistance is critical for assessing ART effectiveness and treatment outcomes for HIV-1-infected individuals, including children, worldwide. Traditionally, testing for HIV-1 drug resistance has primarily been performed on plasma samples, and with commercially available, clinically validated assays that are costly and difficult to access. While plasma is the preferred sample for HIV-1 drug resistance genotyping, plasma analysis requires sophisticated laboratory equipment, personnel, space, and stringent storage conditions for maintenance of sample integrity and transport. With the limitations in feasibility and affordability of providing these ideal conditions for plasma genotyping in resource-constrained settings, the field has gained substantial experience with the dried blood spot (DBS) technique as an alternative. Moreover, DBS analysis can be used to comprehensively monitor the spread of the epidemic with applications to more-sensitive and quantitative technologies to assess HIV-1 globally. [ABSTRACT FROM AUTHOR]

In this fifth decade of the human immunodeficiency virus (HIV) epidemic, central nervous system (CNS) complications including cognitive impairment and mental health remain a burden for people with HIV (PWH) on antiretroviral therapy. Despite the persistence of these complications, which often co-occur, the underlying pathophysiology remains elusive and consequently treatments remain limited. To continue to grow our understanding of the underlying mechanisms of CNS complications among PWH, there is a need to reexamine our current approaches, which are now more than 2 decades old. At the 2021 National Institutes of Health–sponsored meeting on Biotypes of CNS Complications in PWH, the Neurobehavioral Working Group addressed the following: (1) challenges inherent to determining CNS complications; (2) heterogeneity in CNS complications; and (3) problems and solutions for examining integrated biotypes. The review below provides a summary of the main points presented and discussed by the Neurobehavioral Working Group at the meeting. [ABSTRACT FROM AUTHOR]

Background: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU).Methods: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders.Results: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms.Conclusions: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU.Clinical Trials Registration: NCT03088410. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV)-1 genetic diversity increases during infection and can help infer the time elapsed since infection. However, the effect of antiretroviral treatment (ART) on the inference remains unknown.Methods: Participants with estimated duration of HIV-1 infection based on repeated testing were sourced from cohorts in Botswana (n = 1944). Full-length HIV genome sequencing was performed from proviral deoxyribonucleic acid. We optimized a machine learning model to classify infections as < or >1 year based on viral genetic diversity, demographic, and clinical data.Results: The best predictive model included variables for genetic diversity of HIV-1 gag, pol, and env, viral load, age, sex, and ART status. Most participants were on ART. Balanced accuracy was 90.6% (95% confidence interval, 86.7%-94.1%). We tested the algorithm among newly diagnosed participants with or without documented negative HIV tests. Among those without records, those who self-reported a negative HIV test within <1 year were more frequently classified as recent than those who reported a test >1 year previously. There was no difference in classification between those self-reporting a negative HIV test <1 year, whether or not they had a record.Conclusions: These results indicate that recency of HIV-1 infection can be inferred from viral sequence diversity even among patients on suppressive ART. [ABSTRACT FROM AUTHOR]

The spectrum of placental pathology in human immunodeficiency virus (HIV) is vast. Features observed are not only limited to the effects of the virus itself but may include that of coinfections such as tuberculosis and syphilis. The presence of other comorbidities and changes as a result of antiretroviral therapy may further confound the histologic findings. There is a paucity of unbiased information of the effects of maternal HIV on the placenta and how these changes relate to birth outcomes. Antiretroviral therapy, now in widespread use, has altered the course of maternal HIV disease and it is unknown whether this has altered the pathophysiology of HIV on the placenta. HIV-associated placental findings that have been most well described include acute chorioamnionitis, low placental weight, and maternal vascular malperfusion, with a tendency towards lower rates of chronic villitis. [ABSTRACT FROM AUTHOR]

Background: Immune activation persists despite suppressive antiretroviral therapy (ART) and may be affected by sex or body composition. We explored these relationships in a subset of participants who initiated ART in two large randomized trials.Methods: Purposeful sampling selected participants who achieved virologic suppression on ART and either maintained weight within ± 0.5 kg/m2 or gained 2.6-6.4 kg/m2 from baseline to 96 weeks. We measured 7 markers of inflammation and immune activation at weeks 0 and 96. Multivariable linear regression explored associations of weight gain, sex, and pre-ART BMI with pre-ART and changes in biomarker concentrations.Results: 340 participants were selected; median pre-ART age 42 years, CD4+ cell count 273 cells/mm3, HIV-1 RNA 4.7 log10 copies/mL; 49% were women, 33% white, 42% black, and 24% Hispanic. Among participants with a normal pre-ART BMI, higher pre-ART levels of IL-6, sTNF-RI and RII, CXCL-10, sCD163 and hsCRP were associated with weight gain. Association of weight gain with week 96 changes of these biomarkers differed by sex; women who gained weight had smaller declines in most measured biomarkers compared to men who gained.Conclusions: Among women, weight gain is associated with attenuated decline in several immune activation markers following ART initiation. Clinical Trials Registration. NCT00811954 and NCT00811954. [ABSTRACT FROM AUTHOR]

This multicountry prospective study investigated whether persistent systemic inflammation, measured by 8 plasma biomarkers, in HIV-1-infected Africans during suppressive antiretroviral therapy (ART) (viral load <50 copies/mL), was associated with CD4+ T-cell recovery and viral rebound (>1000 copies/mL) during long-term treatment. On-ART sCD14 and C-reactive protein concentrations were inversely associated with subsequent CD4+ T-cell counts. Risk of viral rebound was increased for participants with higher on-ART CXCL10 concentrations and reduced for those with a greater sCD163 decline during the first year of ART. Persistent systemic inflammation predicted CD4+ T-cell recovery and viral rebound, warranting further mechanistic research in relation to clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC).Methods: We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR).Results: Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR.Conclusions: This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization's recommendation to avoid using NNRTIs in countries where levels of PDR are high. [ABSTRACT FROM AUTHOR]

Background: During antiretroviral treatment (ART) with plasma HIV RNA below the limit of quantification, HIV RNA can be detected in genital or rectal secretions, termed discordant shedding (DS). We hypothesized that proliferating cells produce virions without HIV replication.Methods: ART-naive Peruvians initiating ART were observed for DS over 2 years. HIV env and pol genomes were amplified from DS. Antiretrovirals and cytokines/chemokines concentrations were compared at DS and control time points.Results: Eighty-two participants had ART suppression. DS was detected in 24/82 (29%) participants: 13/253 (5%) cervicovaginal lavages, 20/322 (6%) seminal plasmas, and 6/85 (7%) rectal secretions. HIV RNA in DS specimens was near the limit of quantification and not reproducible. HIV DNA was detected in 6/13 (46%) DS cervicovaginal lavages at low levels. Following DNase treatment, 5/39 DS specimens yielded HIV sequences, all without increased genetic distances. Women with and without DS had similar plasma antiretroviral levels and DS in 1 woman was associated with inflammation.Conclusions: HIV RNA and DNA sequences and therapeutic antiretroviral plasma levels did not support HIV replication as the cause of DS from the genital tract. Rather, our findings infer that HIV RNA is shed due to proliferation of infected cells with virion production. [ABSTRACT FROM AUTHOR]

Background: The contribution of immune activation to arterial stiffness and its reversibility in human immunodeficiency virus (HIV)-infected adults in sub-Saharan Africa is unknown.Methods: HIV-uninfected and HIV-infected Malawian adults initiating antiretroviral therapy (ART) with a CD4+ T-cell count of <100 cells/μL were enrolled and followed for 44 weeks; enrollment of infected adults occurred 2 weeks after ART initiation. We evaluated the relationship between carotid femoral pulse wave velocity (cfPWV) and T-cell activation (defined as HLA-DR+CD38+ T cells), exhaustion (define as PD-1+ T cells), and senescence (defined as CD57+ T cells) and monocyte subsets, using normal regression.Results: In 279 HIV-infected and 110 HIV-uninfected adults, 142 (37%) had hypertension. HIV was independently associated with a 12% higher cfPWV (P = .02) at baseline and a 14% higher cfPWV at week 10 (P = .02), but the increases resolved by week 22. CD4+ and CD8+ T-cell exhaustion were independently associated with a higher cfPWV at baseline (P = .02). At 44 weeks, arterial stiffness improved more in those with greater decreases in the percentage of CD8+ T cells and the percentage of PD-1+CD8+ T cells (P = .01 and P = .03, respectively). When considering HIV-infected participants alone, the adjusted arterial stiffness at week 44 tended to be lower in those with higher baseline percentage of PD-1+CD8+ T cells (P = .054).Conclusions: PD-1+CD8+ T-cells are associated with HIV-related arterial stiffness, which remains elevated during the first 3 months of ART. Resources to prevent cardiovascular disease in sub-Saharan Africa should focus on blood pressure reduction and individuals with a low CD4+ T-cell count during early ART. [ABSTRACT FROM AUTHOR]

Background: HIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.Methods: Posttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers.Results: Of the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P < .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ≥1000 copies/mL and 33% had a peak viral load ≥10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ≥5 years.Conclusions: Posttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission. [ABSTRACT FROM AUTHOR]

Background: In human immunodeficiency virus (HIV)-infected patients on combination antiretroviral therapy (cART), lipodystrophy shares many similarities with metabolic syndrome, but only metabolic syndrome has objective classification criteria. We examined adipose tissue changes related to lipodystrophy and metabolic syndrome to clarify whether it may be acceptable to focus diagnosis on metabolic syndrome rather than lipodystrophy.Methods: This is a cross-sectional study of 60 HIV-infected men on cART and 15 healthy men. We evaluated lipodystrophy (clinical assessment) and metabolic syndrome (JIS-2009). We compared adipocyte size, leukocyte infiltration, and gene expression in abdominal subcutaneous adipose tissue biopsies of patients with and without lipodystrophy and with and without metabolic syndrome.Results: Lipodystrophy was only associated with increased macrophage infiltration (P = .04) and adiponectin messenger ribonucleic acid ([mRNA] P = .008), whereas metabolic syndrome was associated with larger adipocytes (P < .0001), decreased expression of genes related to adipogenesis and adipocyte function (P values between <.0001 and .08), increased leptin mRNA (P = .04), and a trend towards increased expression of inflammatory genes (P values between .08 and .6).Conclusions: Metabolic syndrome rather than lipodystrophy was associated with major unfavorable abdominal subcutaneous adipose tissue changes. In a clinical setting, it may be more relevant to focus on metabolic syndrome diagnosis in HIV-infected patients on cART with regards to adipose tissue dysfunction and risk of cardiometabolic complications. [ABSTRACT FROM AUTHOR]

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation. [ABSTRACT FROM AUTHOR]

Background: Tenofovir disoproxil fumarate (TDF) is commonly used in antiretroviral treatment (ART) and pre-exposure prophylaxis regimens. We evaluated the relationship between adverse perinatal outcomes and prenatal TDF use.Methods: Longitudinal data were analyzed from human immunodeficiency virus (HIV)-infected women who became pregnant during 2 HIV prevention studies conducted among HIV-serodiscordant couples in Kenya and Uganda. Pregnancies included were singleton, not terminated by an induced abortion, and had documented 3-drug ART use. Multivariate generalized estimating equation models were used to determine the association of prenatal TDF and perinatal outcomes.Results: The most frequent ART regimens were TDF/3TC/EFV (39%) and AZT/3TC/NVP (34%); 49% of pregnancies had prenatal TDF exposure and 6% used a protease inhibitor. Neonatal death, preterm birth, and pregnancy loss occurred in 2%, 8%, and 12% of pregnancies, respectively. No differences were observed between pregnancies with and without exposure to TDF in the frequency of pregnancy loss (adjusted prevalence rate ratio [aPRR] 1.19, P = .8) or neonatal death (aPRR 0.68, P = .6). Preterm birth occurred less frequently among pregnancies exposed to TDF (aPRR, 0.34, P = .02).Conclusion: Maternal TDF use did not adversely affect perinatal outcomes. [ABSTRACT FROM AUTHOR]

Healthcare delivery has advanced due to the implementation of point-of-care testing, which is often performed within minutes to hours in minimally equipped laboratories or at home. Technologic advances are leading to point-of-care kits that incorporate nucleic acid-based assays, including polymerase chain reaction, isothermal amplification, ligation, and hybridization reactions. As a limited number of single-nucleotide polymorphisms are associated with clinically significant human immunodeficiency virus (HIV) drug resistance, assays to detect these mutations have been developed. Early versions of these assays have been used in research. This review summarizes the principles underlying each assay and discusses strategic needs for their incorporation into the management of HIV infection. [ABSTRACT FROM AUTHOR]

The emergence and spread of human immunodeficiency virus (HIV) drug resistance from antiretroviral roll-out programs remain a threat to long-term control of the HIV-AIDS epidemic in low- and middle-income countries (LMICs). The patterns of drug resistance and factors driving emergence of resistance are complex and multifactorial. The key drivers of drug resistance in LMICs are reviewed here, and recommendations are made to limit their influence on antiretroviral therapy efficacy. [ABSTRACT FROM AUTHOR]

We examined differences in prevalence of linkage to care and antiretroviral (ARV) treatment among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) between 2008 and 2014 in National HIV Behavioral Surveillance. Prevalence of linkage to care increased from 79% in 2008 to 87% in 2014 (prevalence ratio [PR], 1.05; 95% confidence interval [CI], 1.03-1.07). ARV treatment increased from 69% in 2008 to 88% in 2014 (adjusted PR, 1.15; 95% CI, 1.12-1.18). Despite these increases, a large disparity in ARV treatment between white and black MSM remains. Increased resources are needed to support immediate referrals for ARV treatment for all MSM newly diagnosed with HIV. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that the durability of serological response is impaired in successfully vaccinated human immunodeficiency virus-1 (HIV-1) positive subjects after receiving 2 doses of inactivated hepatitis A virus (HAV) vaccine. We evaluated whether 3 doses compared with 2 doses of HAV vaccine could improve the long-term seroprotection for this susceptible group.Methods: Antibody persistence among HIV-positive men who have sex with men aged 18-40 years who had received 2 or 3 doses of HAV vaccine according to a 0-6- or a 0-1-6-month schedule was evaluated biannually for 5 consecutive years in this prospective, nonrandomized cohort study.Results: At the end of 5 years, seroprotection persisted in 79% (146/185) versus 76% (85/110) and 94% (146/155) versus 88% (84/95) of the 3- versus 2-dose primary responders by intention-to-treat and per-protocol analyses, respectively (P > .05). Throughout the 5 years, the geometric mean concentrations of anti-HAV immunoglobulin G (IgG) were significantly higher for the 3-dose than the 2-dose group. In the multivariable analysis, a 3-dose regimen compared with a 2-dose regimen (odds ratio = 3.36; 95% confidence interval = 1.14-9.93) was independently associated with sustained seroprotection.Conclusions: Three doses versus 2 doses of HAV vaccine improve the durability of immune responses in terms of higher concentrations of specific IgG, which take longer to decay to subthreshold levels. [ABSTRACT FROM AUTHOR]

Background:  Diagnosis of human immunodeficiency virus (HIV) infection during early infancy (commonly known as "early infant HIV diagnosis" [EID]) followed by prompt initiation of antiretroviral therapy dramatically reduces mortality. EID testing is recommended at 6 weeks of age, but many infant infections are missed.Design/methods:  We simulated 4 EID testing strategies for HIV-exposed infants in South Africa: no EID (diagnosis only after illness; hereafter, "no EID"), testing once (at birth alone or at 6 weeks of age alone; hereafter, "birth alone" and "6 weeks alone," respectively), and testing twice (at birth and 6 weeks of age; hereafter "birth and 6 weeks"). We calculated incremental cost-effectiveness ratios (ICERs), using discounted costs and life expectancies for all HIV-exposed (infected and uninfected) infants.Results:  In the base case (guideline-concordant care), the no EID strategy produced a life expectancy of 21.1 years (in the HIV-infected group) and 61.1 years (in the HIV-exposed group); lifetime cost averaged $1430/HIV-exposed infant. The birth and 6 weeks strategy maximized life expectancy (26.5 years in the HIV-infected group and 61.4 years in the HIV-exposed group), costing $1840/infant tested. The ICER of the 6 weeks alone strategy versus the no EID strategy was $1250/year of life saved (19% of South Africa's per capita gross domestic product); the ICER for the birth and 6 weeks strategy versus the 6 weeks alone strategy was $2900/year of life saved (45% of South Africa's per capita gross domestic product). Increasing the proportion of caregivers who receive test results and the linkage of HIV-positive infants to antiretroviral therapy with the 6 weeks alone strategy improved survival more than adding a second test.Conclusions:  EID at birth and 6 weeks improves outcomes and is cost-effective, compared with EID at 6 weeks alone. If scale-up costs are comparable, programs should add birth testing after strengthening 6-week testing programs. [ABSTRACT FROM AUTHOR]

The article comments on the paper "Early Virologic Nonresponse to Tenofovir, Abacavir, and Lamivudine in HIV-Infected Antiretroviral-Naive Subjects," by J.E. Gallant, A.E. Rodriguez, and W.G. Weinberg, published in the December 2005 issue of the Journal of Infectious Diseases. The researchers randomized 340 treatment-naive subjects to receive once-daily tenofovir disoproxil fumarate (DF)/abacavir/lamivudine or efavirenz/abacavir/lamivudine. The signature tenofovir DF resistance mutation was found in samples from more than one-half of subjects tested at the time of virologic failure.

We conducted a case-controlled study of the associations of CCR5-Δ32 heterozygosity with human immunodeficiency virus type 1 (HIV-1) reservoir size, lymphocyte activation, and CCR5 expression in 114 CCR5(Δ32/WT) and 177 wild-type CCR5 AIDS Clinical Trials Group participants receiving suppressive antiretroviral therapy. Overall, no significant differences were found between groups for any of these parameters. However, higher levels of CCR5 expression correlated with lower amounts of cell-associated HIV-1 RNA. The relationship between CCR5-Δ32 heterozygosity, CCR5 expression, and markers of HIV-1 persistence is likely to be complex and may be influenced by factors such as the duration of ART. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV)–infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria. Methods HIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach. Results Of 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms. Conclusions Lopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART. Clinical Trials Registration NCT00993031. [ABSTRACT FROM AUTHOR]

Background. Defining the association of non–AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)–infected persons with antiretroviral therapy (ART)–associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.Methods. We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non–AIDS-defining events, defined as myocardial infarction, stroke, non–AIDS-defining cancer, non–AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4+ T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non–AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4+ and CD8+ T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.Results. Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non–AIDS-defining event. Significant associations were also seen between non–AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.Conclusions. Interventional trials to decrease the incidence of non–AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers.Clinical Trials Registration. NCT00001137. [ABSTRACT FROM AUTHOR]

Background. Epstein-Barr Virus (EBV) is involved in a wide range of malignancies, particularly in immunocompromised subjects. In Africa, EBV primary infection occurs during early childhood, but little is known about the EBV load in Human Immunodeficiency Virus type 1 (HIV-1)–infected children.Methods. Blood samples from 213 HIV-1–infected children, 140 of whom were receiving antiretroviral therapy (ART), were collected at the Nsambya Hospital in Kampala, Uganda, and obtained for dried blood spot analysis. Nucleic acids were extracted and analyzed for quantification of EBV types 1 and 2; 16S ribosomal DNA (rDNA), a marker of microbial translocation; and HIV-1 RNA.Results. Ninety-two of 140 children (66%) receiving ART and 57 of 73 ART-naive children (78%) had detectable EBV DNA levels. Coinfection with both EBV types was less frequent in ART-treated children than in ART-naive children (odds ratio, 0.54 [95% confidence interval {CI}, .30–.98]; P = .042). Mean EBV DNA levels (±standard deviation) were lower in the former (3.99 ± 0.59 vs 4.22 ± 0.54 log10 copies/mL; P = .006) and tended to be inversely associated with ART duration. EBV DNA levels were higher in children with an HIV-1 RNA load of > 3 log10 copies/mL of blood (regression coefficient, 0.32 [95% CI, .05–.59]; P = .020) and correlated with circulating 16S rDNA levels (rs = 0.25 [95% CI, .02–.46]; P = .031).Conclusions. These findings suggest that ART, by limiting HIV-1 replication, microbial translocation, and related immune activation, prevents superinfection with both EBV types and keeps EBV viremia down, thus potentially reducing the risk of EBV-associated lymphomas. [ABSTRACT FROM PUBLISHER]

In 2010, the San Francisco Department of Public Health offered antiretroviral therapy (ART) to all its patients with human immunodeficiency virus (HIV) regardless of CD4 count. We assessed trends in time from diagnosis to ART initiation and factors associated with ART initiation among San Francisco residents living with HIV between 2007 and 2011. Time to ART initiation decreased among those diagnosed with higher CD4 count. ART initiation rate was significantly higher in recent years and lower among African Americans, men who have sex with men who also inject drugs, and persons aged ≥50 years. We found a trend toward early treatment. However, racial and social disparities persist. [ABSTRACT FROM AUTHOR]

Background. We sought to quantify the survival benefits attributable to antiretroviral therapy (ART) in South Africa since 2004.Methods. We used the Cost-Effectiveness of Preventing AIDS Complications–International model (CEPAC) to simulate 8 cohorts of human immunodeficiency virus (HIV)–infected patients initiating ART each year during 2004–2011. Model inputs included cohort-specific mean CD4+ T-cell count at ART initiation (112–178 cells/µL), 24-week ART suppressive efficacy (78%), second-line ART availability (2.4% of ART recipients), and cohort-specific 36-month retention rate (55%–71%). CEPAC simulated survival twice for each cohort, once with and once without ART. The sum of the products of per capita survival differences and the total numbers of persons initiating ART for each cohort yielded the total survival benefits.Results. Lifetime per capita survival benefits ranged from 9.3 to 10.2 life-years across the 8 cohorts. Total estimated population lifetime survival benefit for all persons starting ART during 2004–2011 was 21.7 million life-years, of which 2.8 million life-years (12.7%) had been realized by December 2012. By 2030, benefits reached 17.9 million life-years under current policies, 21.7 million life-years with universal second-line ART, 23.3 million life-years with increased linkage to care of eligible untreated patients, and 28.0 million life-years with both linkage to care and universal second-line ART.Conclusions. We found dramatic past and potential future survival benefits attributable to ART, justifying international support of ART rollout in South Africa. [ABSTRACT FROM AUTHOR]

Background. In treatment-naive, human immunodeficiency virus (HIV)–infected persons, combination antiretroviral therapy (cART) incorporating raltegravir (RAL) is highly effective for virologic suppression, but characteristics of immunologic recovery have not been described.Methods. We performed a 48-week substudy of 15 patients, median age 40 years, within a phase 2 randomized trial of RAL-cART in treatment-naive patients with chronic HIV infection.Results. Plasma viral load decreased from 5.2 ± 5.3 log10 HIV RNA copies/mL to 2.2 ± 2.4 log10 copies/mL at week 4, reaching <50 copies/mL at week 8 in 13 of 15 patients. Total CD4 T cells increased at week 4, as did central memory CD4 T cells in association with reduction of the immune activation markers HLA-DR and CD38 and immune exhaustion marker PD1 in CD4 and CD8 T cells. Naive CD4 T cells increased at week 24 with appearance of HIV gag–specific interleukin 2, interferon-γ, and CD107a responses in CD4 and CD8 T cells at week 48. Plasma lipopolysaccharide and soluble CD14 decreased, but at week 48 were elevated as compared to healthy volunteers. Altogether, the week 48 immune profile was more favorable in patients taking RAL-cART than in patients treated with non–RAL-cART.Conclusions. RAL in first-line treatment regimens results in rapid immune reconstitution with residual low-level microbial translocation. [ABSTRACT FROM AUTHOR]

Background. Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS).Methods. We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study.Results. Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02).Conclusions. These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV. [ABSTRACT FROM AUTHOR]

Background. Little is known about mortality of opiate users attending methadone maintenance treatment (MMT) clinics. We sought to investigate mortality and its predictors among human immunodeficiency virus (HIV)–positive MMT clients.Methods. Records of 306 786 clients enrolled in China's MMT program from 24 March 2004 to 30 April 2011 were abstracted. Mortality rates were calculated for all HIV-positive antiretroviral treatment (ART)–naive and ART-experienced clients. Risk factors were examined using stratified proportional hazard ratios (HRs).Results. The observed mortality rate for all clients was 11.8/1000 person-years (PY, 95% confidence interval [CI], 11.5–12.1) and 57.2/1000 PY (CI, 54.9–59.4) for HIV-positive clients (n = 18 193). An increase in average methadone doses to >75 mg/day was associated with a 24% reduction in mortality (HR = 0.76, CI, .70–.82), a 48% reduction for ART-naive HIV-positive clients (HR = 0.52, CI, .42–.65), and a 47% reduction for ART-experienced HIV-positive clients (HR = 0.53, CI, .46–.62). Among ART-experienced clients, initiation of ART when the CD4+ T-cell count was >300 cells/mm3 (HR = 0.64, CI, .43–.94) was also associated with decreased risk of death.Conclusions. We found high mortality rates among HIV-positive MMT clients, yet decreased risk of death, with earlier ART initiation and higher methadone doses. A higher daily methadone dose was associated with reduced mortality in both HIV-infected and HIV-uninfected clients, independent of ART. [ABSTRACT FROM AUTHOR]

Background. Despite viral suppression, antiretroviral therapy (ART) does not restore CD4+ T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1).Methods. In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4+ T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/µL in the CD4+ T-cell count.Results. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4+ T-cell count was 153 cells/µL. The median increase in CD4+ T-cell count from baseline to week 22/24 was 12 cells/µL (90% confidence interval, 1–22). A CD4+ T-cell count increase of at least 20 cells/µL was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc.Conclusions. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4+ T-cell counts of at least 20 cells/µL. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted.Clinical Trials Registration. NCT 00709111. [ABSTRACT FROM AUTHOR]

Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second-line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53% were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure. [ABSTRACT FROM AUTHOR]

Background. PACTG (Pediatric AIDS Clinical Trials Group) 225, a multicenter, randomized, open-label trial in the United States evaluated reactogenicity and immunogenicity of 2 vaccination regimens: monovalent measles vaccine (Attenuvax) at 6 months of age and measles, mumps, and rubella, live attenuated (MMRII) vaccine at 12 months of age (2D), or only MMRII at 12 months of age (1D) in human immunodeficiency virus-infected (HIVinfected) (POS) and uninfected (NEG) children in the pre-highly active antiretroviral therapy (pre-HAART) period. Methods. Plaque-reduction neutralization (PRN) of measles-neutralizing antibody titers were evaluated at study weeks 0, 6, 26, 32, 52, and 130 (∼3 years of age). Results. The 110 subjects included: 65 2DNEG; 30 1DNEG; 7 2DPOS and 8 1DPOS. Vaccinations (n = 175) were associated with no adverse experiences >Grade 2 except for Grade 3 fever (n = 2, 1 1DPOS and 1 1DNEG). Six weeks after Attenuvax, all 2DPOS subjects (7/7) seroresponded (PRN titers ≥120 mIU/mL) with median titers significantly exceeding 2DNEG titers (2115 vs 628 mIU/mL, respectively; P = .023). At ∼3 years of age, 67% 1DPOS (4/6) and 83% 2DPOS (4/5) subjects maintained titers≥120 mIU/mL. Prevaccination titers≥25 mIU/mL among 2DNEG subjects correlated inversely with the likelihood of achieving titers≥120 mIU/mL (56% vs 90%; P = .004). Conclusions. Among HIV-infected children pre-HAART, Attenuvax at 6 months was well tolerated and immunogenic. These data support the current World Health Organization (WHO) recommendation to administer a first dose of measles vaccine at 6 months of age to HIV-infected children. [ABSTRACT FROM AUTHOR]

Background. Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults. Methods. T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Women's Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38+HLA-DR+) and senescence (CD28-CD57+) with subclinical carotid artery disease. Results. Compared with HIV-uninfected women, frequencies of CD4+CD38+HLA-DR+, CD8+CD38+HLA-DR+, and CD8+CD28-CD57+ T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4+ and CD8+ T cells and immunosenescent CD8+ T cells were associated with increased prevalence of carotid artery lesions (prevalence ratiolesions associated with activated CD4+ T cells, 1.6 per SD [95% confidence interval {CI}, 1.1-2.2]; P 5 .02; prevalence ratiolesions associated with activated CD8+ T cells, 2.0 per SD [95% CI, 1.2-3.3]; P < .01; prevalence ratiolesions associated with senescent CD8+ T cells, 1.9 per SD [95% CI, 1.1-3.1]; P = .01). Conclusions. HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy. [ABSTRACT FROM AUTHOR]

Background. PRO 140 is a humanized CCR5 monoclonal antibody that has demonstrated potent antiviral activity when it is administered intravenously to adults infected with CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1). This study is the first to evaluate subcutaneous administration. Methods. A randomized, double-blind, placebo-controlled study was conducted among 44 subjects with HIV- 1 RNA levels of >5000 copies/mL, CD4+ cell counts of 1300 cells/mL, no receipt of antiretroviral therapy for ⩾12 weeks, and only R5 HIV-1 detectable. Subjects received placebo, 162 mg of PRO 140, or 324 mg of PRO 140 weekly for 3 weeks or 324 mg of PRO 140 every other week for 2 doses by means of subcutaneous infusion. Subjects were monitored for 58 days for safety, antiviral effects, and PRO 140 serum concentrations. Results. Subcutaneous PRO 140 demonstrated potent and prolonged antiretroviral activity. Mean log10 reductions in HIV-1 RNA level were 0.23, 0.99 ( P=.009), 1.37 (P < .001), and 1.65 (P < .001) for the placebo, 162 mg weekly, 324 mg biweekly, and 324 mg weekly dose groups, respectively. Viral loads remained suppressed between successive doses. Treatment was generally well tolerated. Conclusions. This trial demonstrates proof of concept for a monoclonal antibody administered subcutaneously in HIV-1 infected individuals. Subcutaneous PRO 140 offers the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration. Trial registration. ClinicalTrials.gov identifier: NCT00642707. [ABSTRACT FROM AUTHOR]

Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4+ T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit. [ABSTRACT FROM AUTHOR]

This study characterized the prevalence and patterns of antiretroviral- drug-resistance mutations according to plasma human immunodeficiency virus type 1 (HIV-1) RNA load in a large population of patients with HIV-1 infection who underwent testing for resistance mutations in routine clinical practice. HIV-1 genotypic resistance test results with linked clinical data were obtained from national resistance and clinical databases in the United Kingdom. Among 7861 tests, detection of ⩾1 resistance mutation was most frequent at viral loads of 300-10,000 copies/mL and decreased statistically significantly at viral loads of >10,000 copies/mL. Major resistance mutations were commonly detected in the subset of tests that were performed among patients with viral loads of <1000 copies/mL (1001 [12.7%] of 7861 tests).We conclude that HIV-1 genotypic resistance testing is informative for patients with low viral loads. [ABSTRACT FROM AUTHOR]

Background. Only 33% of eligible human immunodeficiency virus (HIV)-infected patients in South Africa receive antiretroviral therapy (ART). We sought to estimate the impact of alternative ART scale-up scenarios on patient outcomes from 2007-2012. Methods. Using a simulation model of HIV infection with South African data, we projected HIV-associated mortality with and without effective ART for an adult cohort in need of therapy (2007) and for adults who became eligible for treatment (2008 -2012). We compared 5 scale-up scenarios: (1) zero growth, with a total of 100,000 new treatment slots; (2) constant growth, with 600,000; (3) moderate growth, with 2.1 million; (4) rapid growth, with 2.4 million); and (5) full capacity, with 3.2 million. Results. Our projections showed that by 2011, the rapid growth scenario fully met the South African need for ART; by 2012, the moderate scenario met 97% of the need, but the zero and constant growth scenarios met only 28% and 52% of the need, respectively. The latter scenarios resulted in 364,000 and 831,000 people alive and on ART in 2012. From 2007 to 2012, cumulative deaths in South Africa ranged from 2.5 million under the zero growth scenario to 1.2 million under the rapid growth scenario. Conclusions. Alternative ART scale-up scenarios in South Africa will lead to differences in the death rate that amount to more than 1.2 million deaths by 2012. More rapid scale-up remains critically important. [ABSTRACT FROM AUTHOR]

Background. The present study was undertaken to determine the risk and timing of late postnatal transmission (LPT) of human immunodeficiency virus type 1 (HIV-1). Methods. Breast-fed infants previously enrolled in 2 trials of antiretroviral prophylaxis were monitored in Malawi. Kaplan-Meier and proportional hazard models assessed cumulative incidence and association of factors with LPT. Results. Overall, 98 infants were HIV infected, and 1158 were uninfected. The cumulative risk of LPT at age 24 months was 9.68% (95% confidence interval, 7.80%–11.56%). The interval hazards at 1.5–6, 6–12, 12–18, and 18–24 months were 1.22%, 4.05%, 3.48%, and 1.27%, respectively. Conclusions. The risk of LPT beyond 6 months is substantial. Weaning at 6 months could prevent 185% of LPT. [ABSTRACT FROM AUTHOR]

During the past decade and a half, quantitation of plasma-associated human immunodeficiency virus type 1 (HIV-1) RNA level, or HIV-1 load, has been validated in clinical practice and clinical trials as an important surrogate marker of HIV-1 disease progression and of the potency and durability of antiretroviral regimens. This review highlights some of the history, accomplishments, and impact of Tom Merigan's laboratory on the use of HIV-1 load as a marker, as well as on updating technologies for determining HIV-1 load, their performance, interpretation of the results, and their use in clinical practice. [ABSTRACT FROM AUTHOR]

The association between minor mutations in human immunodeficiency virus (HIV) protease at baseline and development of common primary mutation 90M at virological failure (conferring some resistance to all protease inhibitors [PIs]) was evaluated in 93 previously drug-naive patients experiencing failure of their first PI-based antiretroviral regimens. In logistic regression analysis, the probability of accumulating a new 90M mutation at virological failure was associated with the presence at baseline of minor mutation 36I (naturally occurring in ∼25% of HIV clade Band in >80% of HIV non-clade-B viruses) (adjusted odds ratio, 13.5 [95% confidence interval,1.89–95.6]; ) and, possibly, of 10I/V. This suggests a potential role P = .009 for the presence of 36I at baseline in predicting the appearance of 90M at virological failure. [ABSTRACT FROM AUTHOR]

AIDS Clinical Trials Group study 359 was a controlled study of saquinavir with either ritonavir or nelfinavir, together with delavirdine, adefovir, or both, in indinavir-experienced persons. Saquinavir was common in all study arms, and the study investigated relationships among characteristics of patients, saquinavir area under the curve (AUC) and trough concentrations (Cmin), and virologic response. Concentrations of saquinavir were higher when it was combined with ritonavir than when it was combined with nelfinavir and were lower with adefovir-containing regimens. Females had higher AUC and Cmin values than did males. Higher saquinavir AUC and Cmin values were associated with a greater likelihood of human immunodeficiency virus (HIV) RNA levels ≤500 copies/mL (P = .008) and were better predictors of response than was the saquinavir inhibitory quotient. Males had a lower probability of having HIV RNA levels ≤500 copies/mL at week 16 than did females (28% vs. 42%; adjusted odds ratio, 0.43). In this study, a greater proportion of females had HIV RNA levels ≤500 copies/mL than did males, which can be attributed to higher concentrations of saquinavir in females than in males. [ABSTRACT FROM AUTHOR]

Assesses resistance costs of antiretroviral therapies via measures of future drug options. Indication tha tthe regimen with the highest virologic failure rate preserved greater future drug options; Outcome of antiretroviral therapy trials which may complement traditional clinical, virologic and immunologic end points.

Presents a response by Kenrad E. Nelson, David Vlahov, Cunlin Wang, Steffanie A. Strathdee, and Timothy R. Sterling to a letter to the editor about their article related to Highly active antiretroviral therapy.

Mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) continues to contribute to the global burden of disease despite great advances in antiretroviral (ARV) treatment and prophylaxis. In this review, we discuss the proposed mechanisms of MTCT, evidence for cell-free and cell-associated transmission in different routes of MTCT, and the impact of ARVs on virus levels and transmission. Many population-based studies support a role for cell-associated virus in transmission and in vitro studies also provide some support for this mode of transmission. However, animal model studies provide proof-of-principle that cell-free virus can establish infection in infants, and studies of ARVs in HIV-infected pregnant women show a strong correlation with reduction in cell-free virus levels and protection. ARV treatment in MTCT potentially provides opportunities to better define the infectious form of virus, but these studies will require better tools to measure the infectious cell reservoir. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) may be transmitted through either cell-free virions or leukocytes harboring intracellular HIV in bodily fluids. In recent years, the early initiation of combination antiretroviral therapy leading to virological suppression has resulted in decreased HIV transmission to uninfected partners. Additionally, the efficacy of primary chemoprophylaxis with oral or topical antiretroviral regimens containing tenofovir (with or without emtricitabine) has been demonstrated. However, the efficacy of these approaches may be compromised by suboptimal adherence, decreased drug concentrations in mucosal compartments in women, and genital inflammation. Furthermore, in vitro studies on the effects of tenofovir on cell-associated HIV transmission have produced conflicting results. Preclinical studies suggest that combination preventive approaches may be most effective in stopping the transmission of HIV after mucosal exposure. Since the development of antibodies were found to correlate with protection in the only effective HIV vaccine trial, the administration of preformed mucosal and systemic antibodies may inform the development of safe and effective antibody-based oral, topical, and/or systemic preexposure prophylaxis agents and provide guidance in the development of HIV vaccines that effectively block cell-associated HIV transmission. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about highly active antiretroviral therapy.