Although highly active retroviral therapy (HAART) has been extremely effective in lowering AIDS incidence among patients infected with HIV, certain drugs included in HAART can cause serious mitochondrial toxicities. One of the most frequent adverse events is lipoatrophy, which is the loss of subcutaneous fat in the face, arms, buttocks and/or legs as an adverse reaction to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical symptoms of lipoatrophy resemble those of inherited mitochondrial diseases, which suggests that host mitochondrial genotype may play a role in susceptibility. We analyzed the association between mitochondrial haplogroup and severity of lipoatrophy in HIV-infected European American patients on HAART in the Multicenter AIDS cohort Study (MACS) and found that mitochondrial haplogroup H was strongly associated with increased atrophy (arms: p = 0.007, OR = 1.77, 95% CI = 1.17–2.69 legs: p = 0.037, OR = 1.54 95% CI = 1.03–2.31, and buttocks: p = 0.10, OR = 1.41 95% CI = 0.94–2.12). We also saw borderline significance for haplogroup T as protective against lipoatrophy (p = 0.05, OR = 0.52, 95% CI = 0.20–1.00). These data suggest that mitochondrial DNA haplogroup may influence the propensity for lipoatrophy in patients receiving NRTIs.
lipoatrophy; mitochondrial haplogroup; NRTI; mitochondrial toxicity
Mitochondrial function plays a role in both AIDS progression and highly active antiretroviral therapy (HAART) toxicity, therefore we sought to determine whether mitochondrial (mt) DNA variation revealed novel AIDS Restriction Genes (ARGs), particularly as mtDNA single nucleotide polymorphisms (SNPs) are known to influence regulation of oxidative phosphorylation, reactive oxygen species (ROS) production, and apoptosis.
Retrospective cohort study.
We performed an association study of mtDNA haplogroups among 1833 European American HIV-1 patients from five US cohorts, the Multicenter AIDS Cohort Study (MACS), the San Francisco City Clinic Study (SFCC), Hemophilia Growth and Development Study (HGDS), the Multicenter Hemophilia Cohort Study (MHCS), and the AIDS Linked to Intravenous Experiences (ALIVE) cohort to determine whether the mtDNA haplogroup correlated with AIDS progression rate.
MtDNA haplogroups J and U5a were elevated among HIV-1 infected people who display accelerated progression to AIDS and death. Haplogroups Uk, H3, and IWX appeared to be highly protective against AIDS progression.
The associations found in our study appear to support a functional explanation by which mtDNA variation among haplogroups influencing ATP production, ROS generation, and apoptosis is correlated to AIDS disease progression, however repeating these results in cohorts with different ethnic backgrounds would be informative. These data suggest that mitochondrial genes are important indicators of AIDS disease progression in HIV-1 infected persons.
Mitochondria; AIDS; HIV-1; apoptosis; disease
We attempted to refine the understanding of an association of Y-chromosomal haplogroup I (hg-I) with enhanced AIDS progression that had been previously reported. First, we compared the progression phenotype between hg-I and its phylogenetically closest haplogroup J (hg-J). Then, we took a candidate gene approach resequencing DDX3Y, a crucial autoimmunity gene, in hg-I and other common European Y- chromosome haplogroups looking for functional variants. We extended the genetic analyses to CD24L4 and compared and contrasted the roles of disease based selection, demographic history, and population structure shaping the contemporary genetic landscape of hg-I chromosomes. Our results confirmed and refined the AIDS progression signal to hg-I, though no gene variant was identified that can explain the disease association. Molecular evolutionary and genetic analyses of the examined loci suggested a unique evolutionary history in hg-I, probably shaped by complex interactions of selection, demographic history, and high geographical differentiation leading to the formation of distinct hg-I subhaplogroups that today are associated with HIV/AIDS onset. Clearly, further studies on Y chromosome candidate loci sequencing to discover functional variants and discern the roles of evolutionary factors are warranted.
AIDS progression; CD24L4; DDX3Y; population growth; population structure; selection; Y chromosome
Haplogroup G, together with J2 clades, has been associated with the spread of agriculture, especially in the European context. However, interpretations based on simple haplogroup frequency clines do not recognize underlying patterns of genetic diversification. Although progress has been recently made in resolving the haplogroup G phylogeny, a comprehensive survey of the geographic distribution patterns of the significant sub-clades of this haplogroup has not been conducted yet. Here we present the haplogroup frequency distribution and STR variation of 16 informative G sub-clades by evaluating 1472 haplogroup G chromosomes belonging to 98 populations ranging from Europe to Pakistan. Although no basal G-M201* chromosomes were detected in our data set, the homeland of this haplogroup has been estimated to be somewhere nearby eastern Anatolia, Armenia or western Iran, the only areas characterized by the co-presence of deep basal branches as well as the occurrence of high sub-haplogroup diversity. The P303 SNP defines the most frequent and widespread G sub-haplogroup. However, its sub-clades have more localized distribution with the U1-defined branch largely restricted to Near/Middle Eastern and the Caucasus, whereas L497 lineages essentially occur in Europe where they likely originated. In contrast, the only U1 representative in Europe is the G-M527 lineage whose distribution pattern is consistent with regions of Greek colonization. No clinal patterns were detected suggesting that the distributions are rather indicative of isolation by distance and demographic complexities.
Y-chromosome; haplogroup G; human evolution; population genetics
There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized.
We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals.
HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%.
Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.
Haplogroup E1b1, defined by the marker P2, is the most represented human Y chromosome haplogroup in Africa. A phylogenetic tree showing the internal structure of this haplogroup was published in 2008. A high degree of internal diversity characterizes this haplogroup, as well as the presence of a set of chromosomes undefined on the basis of a derived character. Here we make an effort to update the phylogeny of this highly diverse haplogroup by including seven mutations which have been newly discovered by direct resequencing. We also try to incorporate five previously-described markers which were not, however, reported in the 2008 tree. Additionally, during the process of mapping, we found that two previously reported SNPs required a new position on the tree. There are three key changes compared to the 2008 phylogeny. Firstly, haplogroup E-M2 (former E1b1a) and haplogroup E-M329 (former E1b1c) are now united by the mutations V38 and V100, reducing the number of E1b1 basal branches to two. The new topology of the tree has important implications concerning the origin of haplogroup E1b1. Secondly, within E1b1b1 (E-M35), two haplogroups (E-V68 and E-V257) show similar phylogenetic and geographic structure, pointing to a genetic bridge between southern European and northern African Y chromosomes. Thirdly, most of the E1b1b1* (E-M35*) paragroup chromosomes are now marked by defining mutations, thus increasing the discriminative power of the haplogroup for use in human evolution and forensics.
Successful highly active antiretroviral therapy (HAART) regimens have resulted in substantial improvements in the systemic health of HIV infected persons and increased survival times. Despite increased systemic health, the prevalence of minor HIV-associated cognitive impairment appears to be rising with increased longevity, and it remains to be seen what functional outcomes will result from these improvements. Cognitive impairment can dramatically impact functional ability and day-to-day productivity. We assessed the relationship of quality of life (QOL) and neuropsychological functioning with successful HAART treatment.
In a prospective longitudinal study, subjects were evaluated before instituting HAART (naïve) or before changing HAART regimens because current therapy failed to maintain suppression of plasma viral load (treatment failure). Subjects underwent detailed neuropsychological and neurological examinations, as well as psychological evaluation sensitive to possible confounds. Re-evaluation was performed six months after institution of the new HAART regimen and/or if plasma viral load indicated treatment failure. At each evaluation, subjects underwent ultrasensitive HIV RNA quantitative evaluation in both plasma and cerebrospinal fluid.
HAART successes performed better than failures on measures exploring speed of mental processing (p < .02). HAART failure was significantly associated with increased self-reports of physical health complaints (p < .01) and substance abuse (p < .01). An interesting trend emerged, in which HAART failures endorsed greater levels of psychological and cognitive complaints (p = .06). Analysis between neuropsychological measures and QOL scores revealed significant correlation between QOL Total and processing speed (p < .05), as well as flexibility (p < .05).
Our study investigated the relationship between HIV-associated neurocognitive impairment and quality of life. HAART failures experienced slower psychomotor processing, and had increased self-reports of physical health complaints and substance abuse. Contrariwise, HAART successes experienced improved mental processing, demonstrating the impact of successful treatment on functioning. With increasing life expectancy for those who are HIV seropositive, it is important to measure cognitive functioning in relation to the actual QOL these individuals report. The study results have implications for the optimal management of HIV-infected persons. Specific support or intervention may be beneficial for those who have failed HAART in order to decrease substance abuse and increase overall physical health.
Highly active antiretroviral therapy (HAART) rapidly suppresses human immunodeficiency virus (HIV) viral replication and reduces circulating viral load, but the long-term effects of HAART on viral load remain unclear.
We evaluated HIV viral load trajectories over 8 years following HAART initiation in the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study. The study included 157 HIV-infected men and 199 HIV-infected women who were antiretroviral naïve and contributed 1311 and 1837 semiannual person-visits post-HAART, respectively. To account for within-subject correlation and the high proportion of left-censored viral loads, we used a segmental Bernoulli/lognormal random effects model.
Approximately 3 months (0.30 years for men and 0.22 years for women) after HAART initiation, HIV viral loads were optimally suppressed (ie, with very low HIV RNA) for 44% (95% confidence interval = 39%–49%) of men and 43% (38%–47%) of women, whereas the other 56% of men and 57% of women had on average 2.1 (1.5–2.6) and 3.0 (2.7–3.2) log10 copies/mL, respectively.
After 8 years on HAART, 75% of men and 80% of women had optimal suppression, whereas the rest of the men and women had suboptimal suppression with a median HIV RNA of 3.1 and 3.7 log10 copies/mL, respectively.
The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.
Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI) on chromosome 6.
Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.
To determine the effectiveness of efavirenz vs. nevirapine in initial antiretroviral therapy regimens for adults in sub-Saharan Africa
Observational cohort study
Study subjects were 2,817 HIV-infected, HAART-naïve adults who began nevirapine- or efavirenz-based HAART between January 1998 and September 2004 via a private-sector HIV/AIDS program in nine countries of southern Africa. The primary outcome was time to virologic failure (two measurements of viral loads ≥400 copies/mL). Secondary outcomes included all-cause mortality, time to viral load <400 copies/mL, pharmacy-claim adherence, and discontinuation of nevirapine or efavirenz without virologic failure.
The median follow-up period was 2.0 years (interquartile range 1.2–2.6). Patients started on nevirapine were significantly less likely than those started on efavirenz to achieve high adherence, whether defined as 100% (30.2% vs. 38.1%, p<0.002) or >90% (44.8% vs. 49.4%, p<0.02) pharmacy-claim adherence. In a multivariate analysis, patients on nevirapine had greater risk of both virologic failure (HR 1.52; 95% CI 1.24–1.86), death (2.17; 1.31–3.60), and regimen discontinuation (1.67; 1.32–2.11). Switching from nevirapine to efavirenz had no significant virologic effect, whereas switching from efavirenz to nevirapine resulted in significantly slower time to suppression (HR 0.58, 95% CI 0.35–0.93) and faster time to failure (HR 3.92; 95% CI 1.61–9.55) than remaining on efavirenz.
In initial HAART regimens, efavirenz was associated with superior virologic and clinical outcomes than nevirapine, suggesting that efavirenz might be the preferred non-nucleoside reverse transcriptase inhibitor in resource-limited settings. However, its higher cost and potential teratogenicity are important barriers to implementation.
Effectiveness; HAART; Efavirenz; Nevirapine; Southern Africa
Human Y chromosomes belonging to the haplogroup R1b1-P25, although very common in Europe, are usually rare in Africa. However, recently published studies have reported high frequencies of this haplogroup in the central-western region of the African continent and proposed that this represents a ‘back-to-Africa' migration during prehistoric times. To obtain a deeper insight into the history of these lineages, we characterised the paternal genetic background of a population in Equatorial Guinea, a Central-West African country located near the region in which the highest frequencies of the R1b1 haplogroup in Africa have been found to date. In our sample, the large majority (78.6%) of the sequences belong to subclades in haplogroup E, which are the most frequent in Bantu groups. However, the frequency of the R1b1 haplogroup in our sample (17.0%) was higher than that previously observed for the majority of the African continent. Of these R1b1 samples, nine are defined by the V88 marker, which was recently discovered in Africa. As high microsatellite variance was found inside this haplogroup in Central-West Africa and a decrease in this variance was observed towards Northeast Africa, our findings do not support the previously hypothesised movement of Chadic-speaking people from the North across the Sahara as the explanation for these R1b1 lineages in Central-West Africa. The present findings are also compatible with an origin of the V88-derived allele in the Central-West Africa, and its presence in North Africa may be better explained as the result of a migration from the south during the mid-Holocene.
Central-West Africa; Equatorial Guinea; human male lineages; Y chromosome; haplogroup R-V88; back to Africa hypothesis
Chronic hepatitis B (CH-B) is common among HIV-infected individuals and increases liver-related mortality in the absence of highly active antiretroviral therapy (HAART). The impact of CH-B on long-term HAART outcomes has not been fully characterized.
To address this question, HAART initiators enrolled in the Multicenter AIDS Cohort Study (MACS) were retrospectively analyzed. Subjects were classified by hepatitis B category based on serology at the time of HAART initiation. The association of CH-B with mortality, AIDS defining illnesses, CD4 rise, and HIV suppression was assessed using regression analysis.
Of 816 men followed for a median of 7 years on HAART, 350 were never HBV infected, 357 had past infection, 45 had CH-B, and 64 were only core-antibody positive. Despite HAART, AIDS-related mortality was the most common cause of death (8.3/1000 person-years (PYs)). It was highest in those with CH-B (17/1000 PYs, 95% CI 7.3, 42) and lowest among never HBV infected (2.9/1000 PYs, 95% CI 1.4, 6.4). In a multivariable model, patients with CH-B had a 2.7-fold higher incidence of AIDS-related mortality compared to those never infected (P=0.08). Non-AIDS-related mortality was also highest among those with CH-B (22/1000 PYs), primarily due to liver disease (compared to never infected, adjusted HR 4.1, p=0.04). There was no significant difference in AIDS defining events, HIV RNA suppression, and CD4 increase.
In HIV-infected patients receiving long-term HAART, HBV status did not influence HIV suppression or CD4 increase. However, mortality was highest among those with CH-B and was mostly due to liver disease despite HBV-active HAART.
hepatitis B; HIV; HAART; CD4; mortality; isolated core hepatitis B
The role of climate in driving selection of mtDNA as Homo sapiens migrated out of Africa into Eurasia remains controversial. We evaluated the role of mtDNA variation in resting metabolic rate (RMR) and total energy expenditure (TEE) among 294 older, community-dwelling African and European American adults from the Health, Aging and Body Composition Study. Common African haplogroups L0, L2 and L3 had significantly lower RMRs than European haplogroups H, JT and UK with haplogroup L1 RMR being intermediate to these groups. This study links mitochondrial haplogroups with ancestry-associated differences in metabolic rate and energy expenditure.
Metabolic rate; Energetics; Mitochondria; Mitochondrial haplogroups; mtDNA; Oxidative phosphorylation
Highly active antiretroviral therapy (HAART) has allowed many HIV-infected patients to enjoy longer survival and a better quality of life. We performed an economic analysis to estimate the cost-effectiveness of HAART regimens in Italy for managing HIV-naïve infected patients with a viral load below 100,000 copies/mL.
Patients and methods
The population considered in the model consisted of adult subjects with an HIV viral load below 100,000 copies/mL who received antiretroviral HAART treatment for the first time, according to the Italian National Guidelines with recommendation grade A1. The incremental cost-effectiveness analysis of quality-adjusted life years (QALYs) was carried out by means of a Markov model. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. The point of view of the analysis was that of the Italian national health service.
The tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) single-tablet regimen (STR) (€7,417.00) revealed the lowest mean treatment cost. TDF/FTC + raltegravir (RAL) showed a better quality of life (0.906 QALY/year), followed by TDF/FTC/RPV (STR; 0.900 QALY/year), TDF/FTC + RPV (multipill regimen) (0.889 QALY/year), and TDF/FTC + atazanavir (ATV/r) (0.886 QALY/year). TDF/FTC/RPV (STR) appeared to be the most cost-effective therapeutic choice (€13,655.00), followed by TDF/FTC + RPV (multipill regimen) (€15,803.00), and TDF/FTC + efavirenz (EFV) (€16,181.00). The sensitivity analysis on the main variables confirmed the validity of the base case scenario.
STR (TDF/FTC/RPV) is the most cost-effective treatment strategy compared with the other therapeutic regimens recommended by the Italian guidelines for the treatment of naïve patients with a viral load <100,000 copies/mL. The inclusion of adverse-event management of HIV-infected patients affects the cost-effectiveness ratio of all HAART regimens.
HIV; HAART; single-tablet regimen (STR); Markov model; cost-effectiveness
Sustained combination of HIV prevention strategies is essential to curb the spread of the HIV/AIDS epidemic. The use of highly active antiretroviral therapy (HAART) decreases morbidity and mortality, as well as HIV transmission, among treated individuals. The concept of ‘treatment as prevention’ is dependent on HAART’s ability to sustain HIV-1 RNA virological suppression at the individual and population levels, and has been demonstrated in studies evaluating transmission in mother-to-child, sero-discordant couples and large treated populations. The worldwide expansion of maximally effective antiretroviral drug regimens has been coupled with concerns regarding the magnitude of the financial investment required. However, HAART’s compounding effect on reduced morbidity, mortality and transmission makes the expansion of HAART coverage highly cost-averting. Building on a mathematical model that evaluated the impact of expanded HAART access on viral load in a Canadian setting, we demonstrate that an investment of CA$249 million over the lifetime of treated individuals would result in a net gain of CA$2.1 billion over 30 years. This provides a powerful economic incentive to rapidly scale up HAART access worldwide.
Highly active antiretroviral therapy (HAART); HIV; incidence; mortality; cost-aversion
The ability of the Y chromosome to retain a record of its evolution has seen it become an essential tool of molecular anthropology. In the last few years, however, it has also found use in forensic genetics, providing information on the geographic origin of individuals. This has been aided by the development of efficient screening methods and an increased knowledge of geographic distribution. In this study, we describe the development of single base extension assays used to resolve 61 Y chromosome haplogroups, mainly within haplogroups A, B and E, found in Africa.
Seven multiplex assays, which incorporated 60 Y chromosome markers, were developed. These resolved Y chromosomes to 61 terminal branches of the major African haplogroups A, B and E, while also including a few Eurasian haplogroups found occasionally in African males. Following its validation, the assays were used to screen 683 individuals from Southern Africa, including south eastern Bantu speakers (BAN), Khoe-San (KS) and South African Whites (SAW). Of the 61 haplogroups that the assays collectively resolved, 26 were found in the 683 samples. While haplogroup sharing was common between the BAN and KS, the frequencies of these haplogroups varied appreciably. Both groups showed low levels of assimilation of Eurasian haplogroups and only two individuals in the SAW clearly had Y chromosomes of African ancestry.
The use of these single base extension assays in screening increased haplogroup resolution and sampling throughput, while saving time and DNA. Their use, together with the screening of short tandem repeat markers would considerably improve resolution, thus refining the geographic ancestry of individuals.
Although a dramatic decrease in AIDS progression has been observed after Highly Active Anti Retroviral Therapy (HAART) in both low- and high-resource settings, few data support that fact in low-resource settings.
This study describes the incidence of AIDS-defining illnesses (ADI) after HAART initiation and analyzes their risk factors in a low-resource setting. A focus was put on CD4 cell counts and viral load measurements.
404 HIV-1-infected Senegalese adult patients were enrolled in a prospective observational cohort and data censored as of April 2008. A Poisson regression was used to model the incidence of ADIs over two periods and to assess its association with baseline variables, current CD4, current viral load, CD4 response, and virological response.
ADI incidence declined from 20.5 ADIs per 100 person-years, 95% CI = [16.3;25.8] during the first year to 4.3, 95% CI = [2.3;8.1] during the fourth year but increased afterwards. Before 42 months, the decrease was greater in patients with clinical stage CDC-C at baseline and with a viral load remaining below 1000 cp/mL but was uniform across CD4 strata (p = 0.1). After 42 months, 293 patients were still at risk. The current CD4 and viral load were associated with ADI incidence (decrease of 21% per 50 CD4/mm3 and of 61% for patients with a viral load < 1000 cp/mL).
During the first four years, a uniform decline of ADI incidence was observed even in patients with low CD4-cell counts at HAART initiation as long as the viral load remained undetectable. An increase was noted later in patients with immunologic and virological failures but also in patients with only virological failure.
To examine response to highly active antiretroviral therapy (HAART) among a sample of treatment-experienced patients in the late stage of human immunodeficiency virus (HIV) infection in residential health care facilities (RHCFs) in New York City facilities designated for HIV/AIDS (acquired immunodeficiency syndrome) when access and adherence are maximized.
Medical record review of 111 patients.
Demographics were mean age 42 years; 58% male; 60% African-American; 31% Hispanic; 57% injection drug users (IDUs); 23% with history of dementia; 52% hepatitis C virus (HCV) antibody seropositive; 80% on HAART, of whom 18% had lipodystrophy. Of 88 patients on HAART, 52% had a decreased viral load (>1/2log) versus 13% of 23 not on HAART (P<.05); a>1/2log viral load increase was seen in 8% and 35%, respectively (P<.05). Those with viral load increase were more likely than those with stable/decreased viral load to be IDUs (71% vs. 64%) and to have HCV seropositivity (86% vs. 53%), even with similar initial CD4+ cell count, viral load, and follow-up time.
In a predominantly minority IDU population who are treatment experienced, 50% of the patients successfully responded to treatment with supervised therapy. The RHCFs in New York City provide a unique opportunity to examine further factors associated with response to HAART in an environment in which medication administration and adherence are maximized and monitored carefully.
Advanced HIV; HAART; Hepatitis C Seropositivity; IDUs; Residential Health Care Facilities; Substance Abuse; Viral Load
Mitochondrial toxicity is implicated in some treatment-limiting ART complications, and reports of mitochondrial dysfunction in untreated HIV infection suggest ART-independent effects of HIV. Several studies have explored associations between mtDNA haplogroups (patterns of mtDNA polymorphisms) and outcomes of HIV infection and/or ART, but findings have been inconsistent. We systematically review published studies examining mtDNA haplogroups in HIV infected persons to summarize reported outcome associations, and to highlight potential future research directions. We identified 21 articles published from 2005–2013. Multiple different phenotypes were studied; most were ART-associated metabolic outcomes (e.g. lipodystrophy, insulin resistance, and dyslipidemia). Haplogoup H was associated with the most outcomes, including AIDS progression, CD4 T cell recovery, cirrhosis (in hepatitis C co-infection), and metabolic outcomes. This review is the first to focus on the emerging area of mtDNA haplogroups in HIV, and summarizes the published literature on associations between mtDNA haplogroups and clinical outcomes in populations of European and African descent. Several reported associations require replication and ideally biological verification before definitive conclusions can be drawn, but research in this area has the potential to explain outcome disparities and impact clinical management of patients.
HIV; Mitochondrial DNA; Haplogroups; Antiretroviral Therapy
Aims: To assess the "real life" effectiveness of different antiretroviral therapies (ART).
Methods: A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study A), and in 61 HIV-1 infected children on the evolution of the most relevant markers of progression (study B). All children were categorised into four groups: untreated (NT); on monotherapy (MT); on combination therapy (dual-ART); and on potent ART (HAART).
Results: No child in the HAART group progressed to AIDS, whereas 14 children in the NT and seven in the MT groups progressed to AIDS, respectively, the differences being statistically significant. There was a mean increase of 8 units of %CD4+ per year; this was greater in the HAART group than in the other groups. The mean decrease in viral load was 0.65 log10 copies/ml per year; this was greater in the HAART group than in the NT and MT groups. The HAART group had the lowest probability of returning to baseline %CD4+ and viral load.
Conclusion: Potent ART had the greatest protective effect against progression to AIDS in this observational study.
Long-term remission of HIV-1 disease can be readily achieved by combinations of highly effective antiretroviral therapy (HAART). However, a residual persistent immune activation caused by circulating non infectious particles or viral proteins is observed under HAART and might contribute to an higher risk of non-AIDS pathologies and death in HIV infected persons. A sustained immune activation supports lipid dysmetabolism and increased risk for development of accelerated atehrosclerosis and ischemic complication in virologically suppressed HIV-infected persons receiving HAART.
While several HIV proteins have been identified and characterized for their ability to maintain immune activation, the role of HIV-p17, a matrix protein involved in the viral replication, is still undefined.
Here, we report that exposure of macrophages to recombinant human p17 induces the expression of proinflammatory and proatherogenic genes (MCP-1, ICAM-1, CD40, CD86 and CD36) while downregulating the expression of nuclear receptors (FXR and PPARγ) that counter-regulate the proinflammatory response and modulate lipid metabolism in these cells. Exposure of macrophage cell lines to p17 activates a signaling pathway mediated by Rack-1/Jak-1/STAT-1 and causes a promoter-dependent regulation of STAT-1 target genes. These effects are abrogated by sera obtained from HIV-infected persons vaccinated with a p17 peptide. Ligands for FXR and PPARγ counteract the effects of p17.
The results of this study show that HIV p17 highjacks a Rack-1/Jak-1/STAT-1 pathway in macrophages, and that the activation of this pathway leads to a simultaneous dysregulation of immune and metabolic functions. The binding of STAT-1 to specific responsive elements in the promoter of PPARγ and FXR and MCP-1 shifts macrophages toward a pro-atherogenetic phenotype characterized by high levels of expression of the scavenger receptor CD36. The present work identifies p17 as a novel target in HIV therapy and grounds the development of anti-p17 small molecules or vaccines.
Epidemiological case-control studies have revealed associations between mitochondrial haplogroups and the onset and/or progression of various multifactorial diseases. For instance, mitochondrial haplogroup T was previously shown to be associated with vascular diseases, including coronary artery disease and diabetic retinopathy. In contrast, haplogroup H, the most frequent haplogroup in Europe, is often found to be more prevalent in healthy control subjects than in patient study groups. However, justifications for the assumption that haplogroups are functionally distinct are rare. Therefore, we attempted to compare differences in mitochondrial function between haplogroup H and T cybrids.
Mitochondrial haplogroup H and T cybrids were generated by fusion of HEK293 cells devoid of mitochondrial DNA with isolated thrombocytes of individuals with the respective haplogroups. These cybrid cells were analyzed for oxidative phosphorylation (OXPHOS) enzyme activities, mitochondrial DNA (mtDNA) copy number, growth rate and susceptibility to reactive oxygen species (ROS). We observed that haplogroup T cybrids have higher survival rate when challenged with hydrogen peroxide, indicating a higher capability to cope with oxidative stress.
The results of this study show that functional differences exist between HEK293 cybrid cells which differ in mitochondrial genomic background.
To evaluate the effects of previously reported host genetics factors that influence cytomegalovirus (CMV) retinitis incidence, progression to AIDS, and efficacy of highly active antiretroviral therapy (HAART) for mortality, retinitis progression, and retinal detachment in patients with CMV retinitis and AIDS in the era of HAART.
Prospective, multicenter, observational study.
Cox proportional hazards model based genetic association tests examined the influence of IL-10R1_S420L, CCR5Δ32, CCR2-V64I, CCR5 P1, and SDF-3`A polymorphisms among patients with mortality, retinitis progression, and retinal detachment. Participants were 203 European American and 117 African American patients with AIDS and CMV retinitis.
European American patients with the CCR5 +.P1.+ promoter haplotype showed increased risk for mortality (HR=1.83; 95% CI: 1.00–3.40; P=0.05). Although the same haplotype also trended for increased risk for mortality in African American patients, the result was not significant (HR=2.28; 95% CI: 0.93–5.60; P=0.07). However, this haplotype was associated with faster retinitis progression in African Americans (HR=5.22; 95% CI: 1.54–17.71; P=0.007). Increased risk of retinitis progression was also evident for African American patients with the SDF1-3′A variant (HR=3.89; 95% CI: 1.42–10.60; P=0.008). In addition, the SDF1-3′A variant increased the retinal detachment risk in this patient group (HR=3.05; 95% CI: 1.01–9.16; P=0.05).
Besides overall immune health, host genetic factors influence mortality, retinitis progression, and retinal detachment in patients with AIDS and CMV retinitis that are receiving HAART.
Little is known about pregnancy patterns and levels of HIV RNA in HIV-infected women conceiving on highly-active antiretroviral therapy (HAART) with non-suppressed viral load (VL), nor their therapeutic management.
Linear mixed models were fitted to study changes in VL and potential associated factors including HAART type/duration and immune status among 127 women receiving HAART at conception with detectable VL enrolled in the prospective European Collaborative Study.
Median duration of HAART at conception was 10 months. Seventy-eight (61%) women conceived on PI-based HAART. Seventy-two (57%) women remained on the same HAART regimen throughout pregnancy, 24 (19%) switched regimens and 31 (24%) interrupted HAART during early pregnancy. The intention-to-treat model indicated constant VL up to 10 gestational weeks; thereafter levels decreased significantly, by 0.06 log10 copies/ml weekly until delivery. At baseline, immune status was significantly associated with HIV RNA levels. Excluding treatment-interrupters, there was no significant difference in VL slope between women who did and did not modify their HAART regimens (p=0.14); women conceiving on NNRTI-based HAART had consistently lower VL throughout pregnancy than those on PI-based HAART (p=0.02). Most (64/103, 62%) women had detectable VL within four weeks of delivery (median 2.40 log10 copies/ml). The MTCT rate overall was 1.72% (95%CI 0.21-6.1%).
Practices regarding management of women conceiving on HAART with detectable VL vary in Western Europe. The existence of this group of pregnant women highlights the need for improved monitoring of and support for treated women before they become pregnant, as well as during pregnancy itself.
HIV; pregnancy; HIV RNA; HAART
Objectives To explore the association between a stable partnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy (HAART).
Design Prospective cohort study of adults with HIV (Swiss HIV cohort study).
Setting Seven outpatient clinics throughout Switzerland.
Participants The 3736 patients in the cohort who started HAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years).
Main outcome measures Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least 50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viral rebound.
Results During follow up 2985 (80%) participants reported a stable partnership on at least one occasion. When starting HAART, 52% (545/1042) of participants reported a stable partnership; after five years of follow up 46% (190/412) of participants reported a stable partnership. In an analysis stratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers for Disease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS or death was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnership compared with those without. Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) for progression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/μl or more, and 1.06 (0.98 to 1.14) for optimal viral suppression.
Conclusions A stable partnership is associated with a slower rate of progression to AIDS or death in HIV infected patients receiving HAART.