David Bangsberg and colleagues explore the challenges and rewards of sharing research findings with participants living with HIV enrolled in observational research in rural sub-Saharan Africa.
Host genetic factors are thought to contribute to the interindividual differences in the control of HIV replication. The aim of the present investigation was to determine whether genes encoding GM and KM allotypes—genetic markers of immunoglobulin γ and κ chains, respectively—and those encoding Fcgamma receptor (FcγR) IIa and IIIa are associated with the host control of HIV replication. A case-control design was employed amongst HIV-infected subjects, with a group that spontaneously controlled HIV replication (“controllers”) as cases (n=73) and those who did not control replication, as controls (n=100). Genotyping was done by PCR-RFLP, direct DNA sequencing, and TaqMan® genotyping assays. In Caucasian Americans, certain combinations of FcγR and GM genotypes were differentially distributed between controllers and non-controllers. Among the non-carriers of FcγRIIa arginine allele, GM21 non-carriers had over seven-fold greater odds of being controllers than the carriers of this allele (OR=7.47). These GM determinants also interacted with FcγRIIIa alleles. Among the carriers of the FcγRIIIa valine allele, GM21 non-carriers had over three-fold greater odds of being controllers than the carriers of this allele (OR=3.26). These results show epistatic interactions of genes on chromosomes 14 (GM) and 1 (FcγR) in influencing the control of HIV replication.
GM allotypes; KM allotypes; FcγR; ADCC; HIV
Endothelial progenitor cells (EPCs) are involved in the endothelium repair. Low circulating EPC levels are predictive of cardiovascular events in HIV-negative subjects. The impact of HIV infection on EPCs, and the role of EPCs in HIV-associated cardiovascular disease, is not known. We hypothesized that circulating EPCs would be inversely associated with carotid artery intima-media thickness (c-IMT) changes in HIV-infected subjects.
EPCs (CD34+/KDR+, CD133+/KDR+ and CD34+/CD133+/KDR+) were defined retrospectively by flow cytometry in cryopreserved peripheral blood mononuclear cells collected longitudinally from 66 chronic HIV-infected subjects and cross-sectionally from 50 at-risk HIV-negative subjects. The HIV-infected subjects participated in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort, were receiving antiretroviral therapy (59/66) and had two sequential measurements of c-IMT 1 year apart. Two distinct groups of HIV-infected subjects were identified a priori: rapid c-IMT progressors (subjects with rapid c-IMT progression, n=13, Δc-IMT>0.2 mm) and slow c-IMT progressors (subjects with slow or no c-IMT progression, n=53, Δc-IMT<0.2 mm).
Although cryopreservation reduced sensitivity of detection, EPC frequency in HIV-infected subjects was still significantly higher compared to at-risk HIV-negative subjects (CD34+/KDR+; P=0.01) and correlated positively with CD4+ T-cell count (CD34+/KDR+, r=0.27; P=0.03). No association was found between the change of EPC frequencies over time (ΔEPC) and Δc-IMT or between EPC frequencies and c-IMT or Δc-IMT.
The lack of an association between EPCs and c-IMT in our cohort does not support HIV-associated reductions in EPC frequency as a cause of accelerated atherosclerosis.
To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART.
Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes.
Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from −2.18 to −1.37 ml/min per 1.73 m2 per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m2 was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m2: 3.35 (95% confidence interval (CI) = 1.40–8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type.
ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI.
antiretroviral therapy; chronic kidney disease; tenofovir
HIV/AIDS and food insecurity are two of the leading causes of morbidity and mortality in sub-Saharan Africa, with each heightening the vulnerability to, and worsening the severity of, the other. Less research has focused on the social determinants of food insecurity in resource-limited settings, including social support and HIV-related stigma. In this study, we analyzed data from a cohort of 456 persons from the Uganda AIDS Rural Treatment Outcomes study, an ongoing prospective cohort of persons living with HIV/AIDS (PLWHA) initiating HIV antiretroviral therapy in Mbarara, Uganda. Quarterly data were collected by structured interviews. The primary outcome, food insecurity, was measured with the Household Food Insecurity Access Scale. Key covariates of interest included social support, internalized HIV-related stigma, HIV-related enacted stigma, and disclosure of HIV serostatus. Severe food insecurity was highly prevalent overall (38%) and more prevalent among women than among men. Social support, HIV disclosure, and internalized HIV-related stigma were associated with food insecurity; these associations persisted after adjusting for household wealth, employment status, and other previously identified correlates of food insecurity. The adverse effects of internalized stigma persisted in a lagged specification, and the beneficial effect of social support further persisted after the inclusion of fixed effects. International organizations have increasingly advocated for addressing food insecurity as part of HIV/AIDS programming to improve morbidity and mortality. This study provides quantitative evidence on social determinants of food insecurity among PLWHA in resource-limited settings and suggests points of intervention. These findings also indicate that structural interventions to improve social support and/or decrease HIV-related stigma may also improve the food security of PLWHA.
Uganda; HIV/AIDS; international health; social support; stigma; food security
Many human immunodeficiency virus (HIV) infected individuals suffer from persistent immune activation. Chronic inflammation and immune dysregulation have been associated with an increased risk of age-related diseases even among patients on highly active antiretroviral therapy. The factors leading to immune activation are complex, but have been hypothesized to include persistent viral replication with cellular death as well as microbial translocation across the gastrointestinal tract. Both processes may trigger innate immune responses since many native molecules released from dying cells are similar in structure to pathogen associated molecular patterns. These damage associated molecular patterns include mitochondrial DNA and formylated peptides. We hypothesized that circulating mitochondrial nucleic acid could serve as a biomarker for HIV-associated cell death and drive innate immune activation in infected individuals. We developed a quantitative polymerase chain reaction assay for plasma mitochondrial DNA and validated it on normal blood donors. We then measured mitochondrial DNA levels in acute and chronic HIV infection. While the assay proved to be accurate with a robust dynamic range, we did not find a significant association between HIV disease status and circulating mitochondrial DNA. We did, however, observe a negative correlation between age and plasma mitochondrial DNA levels in individuals with well-controlled HIV.
To assess whether T cell activation independently predicts the extent of CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART).
Prospective cohort study
HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) <400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the % activated (CD38+HLA-DR+) T cells were measured every 3 months.
Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/mm3; and VL, 5.1 log10 copies/ml. Of these, 93% achieved a VL<400 c/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow up at 3 years. Higher pre-ART CD8+ T cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and gender (P=0.017). Thirty-four participants died, 15 after month 6. Each 10 percentage-point increase in activated CD8+ T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pre-therapy CD4 count (P=0.048).
Higher pre-ART CD8+ T cell activation independently predicts slower CD4+ T cell recovery and higher persistent CD8+ T cell activation during ART-mediated viral suppression independently predicts increased mortality among HIV-infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.
HIV; Uganda; Sub-Saharan Africa; T cell activation; Antiretroviral Therapy; Mortality
Although untreated human immunodeficiency virus (HIV)–infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses, it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency.
We compared percentages of activated (CD38+HLA-DR+) T cells between 30 elite controllers, 47 HIV-uninfected individuals, 187 HIV-infected individuals with undetectable viremia receiving antiretroviral therapy (antiretroviral therapy suppressed), and 66 untreated HIV-infected individuals with detectable viremia. Because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection, we also measured plasma lipopolysaccharide (LPS) levels.
Although the median CD4+ cell count in controllers was 727 cells/mm3, 3 (10%) had CD4+ cell counts <350 cells/mm3 and 2 (7%) had acquired immunodeficiency syndrome. Controllers had higher CD4+ and CD8+ cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8+ cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4+ and CD8+ T cell activation was associated with lower CD4+ cell counts (P = .009 and P = .047). Controllers had higher LPS levels than HIV-negative subjects (P < .001), and in controllers higher LPS level was associated with higher CD8+ T cell activation (P = .039).
HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4+ T cell loss even without measurable viremia.
Background. Preventing unintended pregnancies among women living with HIV is an important component of prevention of mother-to-child HIV transmission (PMTCT), yet few data exist on contraceptive use among women entering HIV care. Methods. This was a retrospective study of electronic medical records from the initial HIV clinic visits of 826 sexually active, nonpregnant, 18–49-year old women in southwestern Uganda in 2009. We examined whether contraceptive use was associated with HIV status disclosure to one's spouse. Results. The proportion reporting use of contraception was 27.8%. The most common method used was injectable hormones (51.7%), followed by condoms (29.6%), and oral contraceptives (8.7%). In multivariable analysis, the odds of contraceptive use were significantly higher among women reporting secondary education, higher income, three or more children, and younger age. There were no significant independent associations between contraceptive use and HIV status disclosure to spouse. Discussion. Contraceptive use among HIV-positive females enrolling into HIV care in southwestern Uganda was low. Our results suggest that increased emphasis should be given to increase the contraception uptake for all women especially those with lower education and income. HIV clinics may be prime sites for contraception education and service delivery integration.
Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter-region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation, and lower levels of inflammation-associated viral replication in HIV-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) (r= −0.38, p=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r= −0.41, p=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r= −0.36, p=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 (sCD14) levels during highly active antiretroviral therapy (HAART) (r= 0.38, p=0.007) as well as higher mean viral load off-therapy (r= 0.24, p=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.
Heme oxygenase-1; microsatellite; polymorphism; HIV; soluble CD14; monocytes
Purpose of the review
Given the recent availability of antiretroviral therapy (ART) in resource-limited settings and the significant burden exacted by Kaposi’s sarcoma (KS) in these areas, we reviewed data regarding the impact of ART on KS incidence. We summarized the sizeable literature in resource-rich settings as well emerging data from resource-limited regions. Importantly, we delineated ways impact can be defined, including a) individual patient-level effectiveness; b) population-level effectiveness; c) change in population-level incidence; and d) residual risk of KS.
In resource-rich settings, there are now ample data demonstrating beneficial individual patient-level and population-level effects of ART on KS incidence. There is, however, considerable variability between studies and important methodologic shortcomings. Data from resource-limited settings are much more limited; while they preliminarily indicate individual patient-level effectiveness, they do not yet provide insight on population-level effects.
ART has had a substantial impact on KS incidence in resource-rich settings, but more attention is needed on validly quantifying this effect in order to determine whether additional interventions are needed. Emerging data from resource-limited regions also suggests beneficial impact of ART on KS incidence, but — given the scope of KS in these settings — more data are needed to understand the breadth and magnitude of the effect.
Kaposi’s sarcoma; HIV/AIDS; incidence; antiretroviral therapy; resource-limited settings
Despite burgeoning scientific knowledge about Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi’s sarcoma (KS), little is known about awareness of this virus in the general community. This is particularly the case for men who have sex with men (MSM), the group at greatest risk for infection.
The California Health Interview Survey was a random digit-dial survey of over 50,000 households. Men age 18–64 years who self-identified as gay or bisexual were subsequently re-contacted for a follow-up study of HIV-related knowledge and behavior in which they were asked if they had heard of KS and to describe the cause of KS.
Of 398 MSM interviewed, 73.0% (95% CI: 65.0% to 79.7%) had heard of KS. However, only 6.4% (95% CI: 4.4% to 9.2%) of participants correctly identified that KS is caused by KSHV or a virus other than HIV. Postgraduate education, urban residence, and concurrent HIV infection were all independently associated with greater awareness of the viral origin of KS.
Awareness of KSHV is very low overall among MSM and only somewhat higher, but still unacceptably low, among HIV-infected MSM. Significant efforts are needed to increase awareness of KSHV as a sexually transmitted infection in this subpopulation
men who have sex with men; homosexuality; male; Kaposi sarcoma; herpesvirus 8; human; herpesvirus; Kaposi’s sarcoma-associated; sampling studies
More intensive risk reduction and adherence counseling is necessary for higher-risk PEP users. Without integration into HIV testing and partner services settings, PEP may make an individual impact but is unlikely to make a public health impact.
Background. The National HIV/AIDS Strategy proposes to scale-up post-exposure prophylaxis (PEP). Intensive risk reduction and adherence counseling appear to be effective but are resource intensive. Identifying simpler interventions that maximize the HIV prevention potential of PEP is critical.
Methods. A randomized noninferiority study comparing 2 (standard) or 5 (enhanced) risk reduction counseling sessions was performed. Adherence counseling was provided in the enhanced arm. We measured changes in unprotected sexual intercourse acts at 12 months, compared with baseline; HIV acquisition; and PEP adherence. Outcomes were stratified by degree of baseline risk.
Results. We enrolled 457 individuals reporting unprotected intercourse within 72 h with an HIV-infected or at-risk partner. Participants were 96% male and 71% white. There were 1.8 and 2.3 fewer unprotected sex acts in the standard and enhanced groups. The maximum potential risk difference, reflected by the upper bound of the 95% confidence interval, was 3.9 acts. The difference in the riskier subset may have been as many as 19.6 acts. The incidence of HIV seroconversion was 2.9% and 2.6% among persons randomized to standard and enhanced counseling, respectively, with a maximum potential difference of 3.4%. The absolute and maximal HIV seroconversion incidence was 9.9% and 20.4% greater in the riskier group randomized to standard, compared with enhanced, counseling. Adherence outcomes were similar, with noninferiority in the lower risk group and concerning differences among the higher-risk group.
Conclusions. Risk assessment is critical at PEP initiation. Standard counseling is only noninferior for individuals with lower baseline risk; thus, enhanced counseling should be targeted to individuals at higher risk.
Background. Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting.
Methods. Thirty antiretroviral therapy–treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm3 were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38+ HLA-DR+) CD8+ T cells.
Results. Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134–232) cells/mm3, and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4–12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels.
Conclusions. CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy–mediated CD4+ T cell recovery.
Clinical Trials Registration. NCT00264290.
Background. Some human immunodeficiency virus (HIV)–infected individuals are not able to achieve a normal CD4+ T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size.
Methods. Thirty treated subjects with CD4+ T cell counts of <350 cells/mm3 despite viral suppression for ≥1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38+HLA-DR+CD8+ T cells in peripheral blood mononuclear cells (PBMCs).
Results. The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue.
Conclusions. Low-level viremia is not likely to be a significant cause of suboptimal CD4+ T cell gains during HIV treatment.
Clinical Trials Registration. NCT00631449.
We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons.
Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.
Methods and Results
We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.
Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)
Clinical Trial Registration
URL: http://clinicaltrials.gov. Unique identifier: NCT01519141
AIDS; carotid arteries; inflammation; atherosclerosis
Among HIV controllers, higher activated and HIV-specific CD4+ T cell frequencies were strongly associated with a greater burden of pro-viral DNA, suggesting that the very immune response helping control viral replication may be contributing to viral persistence.
Background. Human immunodeficiency virus (HIV)–-infected individuals maintaining plasma HIV RNA levels <75 copies/mL in the absence of therapy (“HIV controllers”) often maintain high HIV-specific T cell responses, which likely contribute to the control of viral replication. Despite robust immune responses, these individuals never eradicate HIV infection. We hypothesized that HIV-specific CD4+ T cells might serve as target cells for HIV, contributing to viral persistence in this setting.
Methods. We measured frequencies of activated (CD38+ HLA-DR+) and HIV Gag-specific CD4+ and CD8+ T cells and plasma- and cell-associated levels of HIV RNA and DNA in a cohort of 38 HIV controllers.
Results. Although there was no evidence of a relationship between the extent of low-level viremia and the frequency of either activated or HIV-specific CD4+ T cells, controllers with higher HIV-specific CD4+ T cell frequencies had higher cell-associated HIV DNA levels (ρ = 0.53; P = .019). Higher activated CD4+ T cell frequencies were also associated with higher levels of cell-associated DNA (P = .027) and RNA (P = .0096). However, there was no evidence of a relationship between cell-associated HIV RNA or DNA levels and HIV-specific CD8+ T cell frequencies.
Conclusions. These data support a model in which strong HIV-specific CD4+ T cell responses in HIV controllers, while contributing to a potent adaptive immune response, may also contribute to viral persistence, preventing the natural eradication of HIV infection.
Equatorial Africa has among the highest incidences of Kaposi’s sarcoma (KS) in the world, thus earning the name “KS Belt.” This was the case even prior to the HIV . To date, there is no clear evidence that HHV-8 seroprevalence is higher in this region, but interpretation of the available literature is tempered by differences in serologic assays used across studies. We examined representatively sampled ambulatory adults in Uganda, which is in the “KS Belt”, and in Zimbabwe and South Africa which are outside the Belt, for HHV-8 antibodies. All serologic assays were uniformly performed in the same reference laboratory by the same personnel. In the base-case serologic algorithm, seropositivity was defined by reactivity in an immunofluorescence assay or in two enzyme immunoassays. A total of 2375 participants were examined. In Uganda, HHV-8 seroprevalence was high early in adulthood (35.5% by age 21) without significant change thereafter. In contrast, HHV-8 seroprevalence early in adulthood was lower in Zimbabwe and South Africa (13.7% and 10.8%, respectively), but increased with age. After age adjustment, Ugandans had 3.24-fold greater odds of being HHV-8-infected than South Africans (p<0.001) and 2.22-fold greater odds than Zimbabweans (p<0.001). Inferences were unchanged using all other serologic algorithms evaluated. In conclusion, HHV-8 infection is substantially more common in Uganda than in Zimbabwe and South Africa. These findings help explain the high KS incidence in the “KS Belt” and underscore the importance of a uniform approach to HHV-8 antibody testing.
In resource-limited settings—where a massive scale up of HIV services has occurred in the last 5 years—both understanding the extent of and improving retention in care presents special challenges. First, retention in care within the decentralizing network of services is likely higher than existing estimates that account only for retention in clinic, and therefore antiretroviral therapy services may be more effective than currently believed. Second, both magnitude and determinants of patient retention vary substantially and therefore encouraging the conduct of locally relevant epidemiology is needed to inform programmatic decisions. Third, socio-structural factors such as program characteristics, transportation, poverty, work/child care responsibilities, and social relations are the major determinants of retention in care, and therefore interventions to improve retention in care should focus on implementation strategies. Research to assess and improve retention in care for HIV-infected patients can be strengthened by incorporating novel methods such as sampling-based approaches and a causal analytic framework.
HIV care and treatment; retention in care; resource-limited settings; loss to follow-up; access to care
Highly active antiretroviral therapy (HAART) can effectively reduce plasma HIV RNA levels to below the level of detection in most HIV-infected patients. The degree to which residual low-level viremia persists during HAART remains unclear.
We identified 180 subjects (median duration of HIV infection 12 years) who had ≥2 consecutive plasma HIV-1 RNA levels below the level of detection (<50-75 copies/mL) while taking antiretroviral drugs; 36/180 had been virologically suppressed for >5 years. Longitudinal plasma samples that were taken from these subjects during periods of viral load suppression were selected and analyzed. The isothermal Transcription Mediated Amplification (TMA) (limit of detection <3.5 copies RNA/mL) assay was used to measure persistent viremia. A “detuned” EIA assay was used to obtain quantitative HIV antibody levels.
A total of 1606 TMA assays were performed on 438 specimens in 180 HAART-suppressed subjects (median 3 replicates per specimen). In the first year of viral suppression, plasma RNA levels declined significantly (p=0.001), but after month 12 there was no evidence for a continued decline (p=0.383). In the first year of viral suppression, HIV antibody levels also declined (p=0.054), but after month 12 there was no evidence for a continued decline (p=0.988).
Viremia continued to decline during the first 12 months after viremia became undetectable using conventional methods, and then remained stable. HIV antibody levels also decreased in the first year of viral suppression and then remained stable. Viremia and the HIV-associated host response appear to achieve a steady-state “set-point” during long-term combination therapy.
Residual viremia; HAART-suppressed; HIV antibody levels
Although integrase inhibitors are highly effective in the management of drug-resistant HIV, some patients fail to achieve durable viral suppression. The long-term consequences of integrase inhibitor failure have not been well-defined.
We identified 29 individuals who exhibited evidence of incomplete viral suppression on a regimen containing an integrase inhibitor (23 raltegravir, 6 elvitegravir). Prior to initiating the integrase inhibitor-based regimen, the median CD4+ T cell count and plasma HIV RNA levels were 62 cells/mm3 and 4.65 log10 copies/mL, respectively.
At the first failure time-point, the most common integrase resistance pattern for subjects taking raltegravir was wild-type, followed in order of frequency by Q148H/K/R+G140S, N155H, and Y143R/H/C. The most common resistance pattern for subjects taking elvitegravir was E92Q. Long-term failure was associated with continued viral evolution, emergence of high-level phenotypic resistance, and a decrease in replicative capacity.
Although wild-type failure during early integrase inhibitor failure is common, most patients eventually develop high level phenotypic drug resistance. This resistance evolution is gradual and associated with declines in replicative capacity.
integrase inhibitors; drug resistance; virologic failure
Eight percent of the human genome is composed of human endogenous retroviruses (HERVs), which are thought to be inactive remnants of ancient infections. Previously, we showed that individuals with early HIV-1 infection have stronger anti-HERV T cell responses than uninfected controls. In this study, we investigated whether these responses persist in chronic HIV-1 infection and whether they have a role in the control of HIV-1. Peripheral blood mononuclear cells (PBMCs) from 88 subjects diagnosed with HIV-1 infection for at least 1 year (median duration of diagnosis, 13 years) were tested for responses against HERV peptides in gamma interferon (IFN-γ) enzyme immunospot (ELISPOT) assays. Individuals who control HIV-1 viremia without highly active antiretroviral therapy (HAART) had stronger and broader HERV-specific T cell responses than HAART-suppressed patients, virologic noncontrollers, immunologic progressors, and uninfected controls (P < 0.05 for each pairwise comparison). In addition, the magnitude of the anti-HERV T cell response was inversely correlated with HIV-1 viral load (r2 = 0.197, P = 0.0002) and associated with higher CD4+ T cell counts (r2 = 0.072, P = 0.027) in untreated patients. Flow cytometric analyses of an HLA-B51-restricted CD8+ HERV response in one HIV-1-infected individual revealed a less activated and more differentiated phenotype than that stimulated by a homologous HIV-1 peptide. HLA-B51 tetramer dual staining within this individual confirmed two different T cell populations corresponding to these HERV and HIV-1 epitopes, ruling out cross-reactivity. These findings suggest a possible role for anti-HERV immunity in the control of chronic HIV-1 infection and provide support for a larger effort to design an HIV-1 vaccine that targets conserved antigens such as HERV.