Is the clinical course of HIV-1 changing? Cohort study.

OBJECTIVE: To assess whether the clinical course of HIV infection has changed from 1985 to 1995. DESIGN: Cohort Study. SETTING: Infectious disease clinic. SUBJECTS: 285 patients recruited from September 1985 to January 1995 with < or = 12 months between the dates of their last seronegative and first seropositive test result and with first follow up visit in the six months after seroconversion and at least 12 months'' follow up. Patients were grouped according to the date of seroconversion. MAIN OUTCOME MEASURES: Time to CD4 cell count of < 500, 400, and 200 x 10(6) cells/l, and clinical outcome defining AIDS; variation in cell count per day between consecutive visits, and ratio between this variation and time from estimated date of seroconversion at each visit. RESULTS: The groups were similar in age, number with acute primary HIV infection, CD4 cell count at intake, and cell count at the beginning of antiretroviral treatment; they differed in sex ratio, risk factors for HIV, probability of CD4 cell decline to < 500, 400, and 200 x 10(6) cells/l. and risk of developing AIDS. Acute infection, seroconversion after December 1989, and serum beta 2 microglobulin > 296 nmol/l were independent predictors of poor clinical course. The speed of CD4 cell decline, expressed as cell variation divided by the number of days between consecutive visits, increased with more recent seroconversion (P = 0.02). Ratio between the speed of CD4 cell decline and time from estimated date of seroconversion at each visit was also higher in the patients who seroconverted after December 1989. CONCLUSIONS: The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection.     

HIV disease progression in 854 women and men infected through injecting drug use and heterosexual sex and followed for up to nine years from seroconversion. Italian Seroconversion Study.

OBJECTIVE--To compare the progression of HIV-1 infection in men and women followed up for up to nine years after an accurately estimated date of seroconversion. DESIGN--Prospective observational study. SETTING--16 HIV outpatient clinics across Italy. SUBJECTS--321 women and 533 men infected with HIV through injecting drug use or heterosexual sex and with accurately estimated dates of seroconversion. MAIN OUTCOME MEASURES--Progression to severe CD4 lymphocytopenia (CD4 lymphocyte count < 200 x 10(6)/l), development of AIDS defining diseases, and death from AIDS. RESULTS--Thirty two women and 67 men developed AIDS at Kaplan-Meier progression rates of 25% (95% confidence interval 13.8% to 35.5%) and 23% (15.6% to 30.4%), respectively, 7 years after seroconversion. In a Cox proportional hazards model the relative hazard was 0.93 (that is, a slightly lower hazard in women) before and 1.10 (0.70 to 1.72) after adjusting for age, HIV exposure group, and year of seroconversion. When CD4 lymphocytopenia and death from AIDS were used as end points the results were similar, with adjusted relative hazards of 0.95 (0.63 to 1.42) and 0.72 (0.48 to 1.79) respectively. In both women and men the risk of developing AIDS before the CD4 lymphocyte count had declined below 200 x 10(6)/l was small (3% in women, 6% in men). The estimated median count at which AIDS developed in women (34 x 10(6)/l; 10 x 10(6) to 44 x 10(6)) was similar to that for men (44 x 10(6)/l; 22 x 10(6) to 60 x 10(6)). CONCLUSION--There seems to be little evidence for appreciable differences in the natural course of HIV infection between men and women followed up from the time of seroconversion.     

Use of CD4 lymphocyte count to predict long-term survival free of AIDS after HIV infection.

OBJECTIVE--To estimate the probability of remaining free of AIDS for up to 25 years after infection with HIV by extrapolation of changes in CD4 lymphocyte count. DESIGN--Cohort study of subjects followed from time of HIV seroconversion until 1 January 1993. Creation of model by using extrapolated linear regression slopes of CD4 count to predict development of AIDS after 1993. SETTING--Regional haemophilia centre in teaching hospital. SUBJECTS--111 men with haemophilia infected with HIV during 1979-85. Median length of follow up 10.1 years, median number of CD4 counts 17. The model was not fitted for three men because only one CD4 measurement was available. MAIN OUTCOME MEASURES--Development of AIDS. INTERVENTIONS--From 1989 prophylaxis against candida and Pneumocystis carinii pneumonia and antiretroviral drugs when CD4 count fell below 200 x 10(6)/l. RESULTS--44 men developed AIDS up to 1 January 1993. When AIDS was defined as a CD4 count of 50 x 10(6)/l the model predicted that 25% (95% confidence interval 16% to 34%) would survive for 20 years after seroconversion and 18% (11% to 25%) for 25 years. Changing the CD4 count at which AIDS was assumed to occur did not alter the results. Younger patients had a higher chance of 20 year survival than older patients (32% (12% to 52%) for those aged < 15, 26% (14% to 38%) for those aged 15-29, and 15% (0% to 31%) for those aged > or = 30). CONCLUSIONS--These results suggest that even with currently available treatment up to a quarter of patients with HIV infection will survive for 20 years after seroconversion without developing AIDS.     

HIV-specific IL-10-positive CD8+ T cells are increased in advanced disease and are associated with decreased HIV-specific cytolysis

IL-10-producing T cells have been shown to inhibit Ag-specific CD8+ T cell responses, and may play a role in the immune dysregulation observed in HIV-1 infection. We characterized the Gag-specific IL-10 responses by CD8+ T cells in HIV-1-positive volunteers from Uganda. HIV-specific IL-10 responses were detected in 32 of 61 (52.4%) antiretroviral naive and 2 of 15 (13.3%) volunteers with a complete virologic response on antiretroviral therapy (< 400 copies/ml). The frequency of HIV-specific IL-10-positive cells was significantly higher in volunteers with advanced disease (CD4+ T cell count <200 cells/mm3; p = 0.0004), and correlated positively with plasma HIV RNA (r = 0.43, p = 0.0004). Interestingly, the frequency of Gag-specific CD107a/b-, but not IFN-gamma-, positive cells was significantly lower in individuals with detectable IL-10-positive CD8+ T cells (p = 0.004). Gag-specific IL-10-positive CD8+ T cells demonstrated a pattern of surface memory marker expression that is distinct compared with CD107a/b- and IFN-gamma-positive CD8+ T cell populations (p < 0.0001). Our study describes a distinct population of IL-10-positive CD8+ T cells that may play a role in HIV-associated immune dysfunction.     

Does symptomatic primary HIV-1 infection accelerate progression to CDC stage IV disease,CD4 count below 200 x 10(6)/l,AIDS, and death from AIDS?

OBJECTIVE--To investigate the prognostic significance of symptomatic primary HIV-1 infection. DESIGN--Prospective study of homosexual men seroconverting to HIV in 1985 and 1986. Patients were followed up at least three times yearly with clinical examinations and T cell subset determinations for an average of 7.2 years. SETTING--Research project centred on attenders for treatment and screening for HIV at the Karolinska Institute, Stockholm. SUBJECTS--19 patients presenting with a glandular-fever-like illness associated with seroconversion to HIV and 29 asymptomatic seroconverters. MAIN OUTCOME MEASURES--Progression to Centers for Disease Control and Prevention stage IV disease, CD4 cell count below 200 x 10(6)/l, AIDS, and death from AIDS. RESULTS--Symptomatic seroconverters were significantly more likely to develop Centers for Disease Control and Prevention stage IV disease (95% v 66%), CD4 cell counts below 200 x 10(6)/l (84% v 55%), and AIDS (58% v 28%) and die of AIDS (53% v 7%). CONCLUSION--A glandular-fever-like illness associated with seroconversion to HIV-1 predicts accelerated progression to AIDS and other HIV related diseases.     

Incidence and Associated Factors of HIV Drug Resistance in Chinese HIV-Infected Patients Receiving Antiretroviral Treatment

Background

A critical indicator of the future success of highly active antiretroviral therapy (HAART) is the incidence of HIV drug resistance, which has not been studied in China on the national scale.

Methods

HIV drug resistance baseline survey was conducted in the eight provinces with the largest numbers of patients on HAART in 2009, and a prospective cohort study with 12-month follow-up was completed in 2010. Patients completed an interviewer-administrated questionnaire and provided blood for CD4+ T-lymphocyte count (CD4 count), HIV viral load (VL), and HIV drug resistance genotyping. Factors associated with incidence of HIVDR were identified by Cox regression analysis.

Results

The overall prevalence of HIV RNA ≥1000 copies/ml and HIVDR at baseline was 12.4% and 5.6%, respectively. Incidence of HIVDR in the one year follow-up was 3.5 per 100 person years. Independently associated factors were started treatment with a didanosine-based regimen, received care at township hospital or village clinic, low baseline CD4 counts, and high baseline VL.

Conclusions

The incidence of HIVDR in China was higher than that of some developed countries. China urgently needs to provide comprehensive education and training to doctors at village clinics and township hospitals to improve quality community-based care and treatment.     

Lack of evidence for changing virulence of HIV-1 in North America

Background

Several long-term cohort studies and in-vitro fitness assays have resulted in inconsistent reports on changes in HIV-1 virulence, including reports of decreasing, stable, and increasing virulence over the course of the AIDS pandemic. We tested the hypothesis of changing HIV-1 virulence by examining trends in prognostic clinical markers of disease progression from 1984 to 2005 among nearly 400 antiretroviral-naïve participants in the United States Multicenter AIDS Cohort Study (MACS), a longitudinal study of HIV infection in men who have sex with men (MSM).

Methodology/Principal Findings

Because clinical AIDS endpoints could not be used (due to antiretroviral therapies and prophylaxis), three prognostic markers of disease progression were used as proxies for HIV-1 virulence: plasma viral RNA load and CD4+ T cell count at “set point” (between ∼9 and ∼15 months after seroconversion), and rate of CD4 cell decline within three years after seroconversion. We performed multivariate analyses of the association between these markers and seroconversion year, with covariates including MACS site, race/ethnic group, seroconversion age, and CCR5Δ32 status. No statistically significant association was found between year of seroconversion and “set point” plasma viral load (at ∼9 months after seroconversion: slope = −0.004 log₁₀ copies/mL/year, p = 0.76; at ∼15 months: slope = −0.005 log₁₀ copies/mL/year, p = 0.71), CD4 cell count after seroconversion (at ∼9 months: slope = −0.112 cells/µL/year, p = 0.22; at ∼15 months: slope = −0.047 cells/µL/year, p = 0.64), or rate of CD4 cell decline over the first three years after seroconversion (slope = −0.010 cells/ul/yr², p = 0.88).

Conclusions/Significance

The lack of significant trends from 1984 to 2005 in these prognostic markers of HIV disease progression suggests no major change in HIV-1 virulence over the AIDS pandemic in MSM in the US.     

Four drug-HAART in primary HIV-1 infection: clinical benefits and virologic parameters

BACKGROUND: From a theoretical standpoint, primary HIV infection (PHI) represents a great chance to modify the natural history of the disease. In this study we purposed a four drugs regimen with zidovudine, lamivudine, ritonavir and saquinavir to treat aggressively the infection and achieve a complete immune reconstitution. METHODS: This is an Italian multicentric open label study. Adult patients with PHI were eligible for the study if they met at least one clinical criterion and one laboratory criterion of the following. Clinical criteria: Signs and symptoms of acute retroviral syndrome within the past 70 days, exposure to HIV-1 within the last 3 months, a preceding negative antibody test within the past 6 months. Laboratory criteria: Detectable p24 antigen with neutralization in serum; detectable HIV-RNA in plasma; indeterminate Western blot test with negative or low positive value HIV antibody in ELISA test. RESULTS: Since April 1997 to April 1999 40 patients with PHI have been enrolled; 80% of this cohort referred symptoms related to acute antiretroviral syndrome. Treatment has been withdrawn in 17 patients (12 for intolerance, 3 for toxicity and 2 for failure). At baseline the mean CD4+ T cells count and CD4/CD8 ratio were 537 (range 55-1287) and 0.58 (range 0.1-1.03) and the mean plasma HIV-RNA level was 5.9 log copies/ml (range 3-7.15). Plasmatic HIV-1 RNA levels of all patients dropped below 200 copies/ml in 68% of patients at week 12, 81% at week 24, 93% after 12 months and 100% after 18 months. Immunological parameters have been improved and have achieved normal range since 6th month. CONCLUSIONS: A rapid virologic suppression and immunological reconstitution are associated with PHI therapy. However early treatment should be weighted against the potential disadvantages such as immediate adverse events (intolerance and drug toxicity) and long term manifestation (metabolic disorders).     

Impact of Early Initiation of Antiretroviral Therapy in Patients with Acute HIV Infection in Vienna,Austria

BackgroundIt is unclear whether antiretroviral therapy (ART) should be initiated during acute HIV infection. Most recent data provides evidence of benefits of early ART.MethodsWe retrospectively compared the clinical and immunological course of individuals with acute HIV infection, who received ART within 3 months (group A) or not (group B) after diagnosis.ResultsAmong the 84 individuals with acute HIV infection, 57 (68%) received ART within 3 months (A) whereas 27 (32%) did not receive ART within 3 months (B), respectively. Clinical progression to CDC stadium B or C within 5 years after the diagnosis of HIV was less common in (A) when compared to (B) (P = 0.002). After twelve months, both the mean increase in CD4+ T cell count and the mean decrease in viral load was more pronounced in (A), when compared to (B) (225 vs. 87 cells/μl; P = 0.002 and -4.19 vs. -1.14 log10 copies/mL; P<0.001). Twenty-four months after diagnosis the mean increase from baseline of CD4+ T cells was still higher in group A compared to group B (251 vs. 67 cells/μl, P = 0.004).ConclusionsInitiation of ART during acute HIV infection is associated with a lower probability of clinical progression to more advanced CDC stages and significant immunological benefits.     

Viral Load Levels Measured at Set-Point Have Risen Over the Last Decade of the HIV Epidemic in the Netherlands

Background

HIV-1 RNA plasma concentration at viral set-point is associated not only with disease outcome but also with the transmission dynamics of HIV-1. We investigated whether plasma HIV-1 RNA concentration and CD4 cell count at viral set-point have changed over time in the HIV epidemic in the Netherlands.

Methodology/Principal Findings

We selected 906 therapy-naïve patients with at least one plasma HIV-1 RNA concentration measured 9 to 27 months after estimated seroconversion. Changes in HIV-1 RNA and CD4 cell count at viral set-point over time were analysed using linear regression models. The ATHENA national observational cohort contributed all patients who seroconverted in or after 1996; the Amsterdam Cohort Studies (ACS) contributed seroconverters before 1996. The mean of the first HIV-1 RNA concentration measured 9–27 months after seroconversion was 4.30 log₁₀ copies/ml (95% CI 4.17–4.42) for seroconverters from 1984 through 1995 (n = 163); 4.27 (4.16–4.37) for seroconverters 1996–2002 (n = 232), and 4.59 (4.52–4.66) for seroconverters 2003–2007 (n = 511). Compared to patients seroconverting between 2003–2007, the adjusted mean HIV-1 RNA concentration at set-point was 0.28 log₁₀ copies/ml (95% CI 0.16–0.40; p<0.0001) and 0.26 (0.11–0.41; p = 0.0006) lower for those seroconverting between 1996–2002 and 1984–1995, respectively. Results were robust regardless of type of HIV-1 RNA assay, HIV-1 subtype, and interval between measurement and seroconversion. CD4 cell count at viral set-point declined over calendar time at approximately 5 cells/mm³/year.

Conclusion

The HIV-1 RNA plasma concentration at viral set-point has increased over the last decade of the HIV epidemic in the Netherlands. This is accompanied by a decreasing CD4 cell count over the period 1984–2007 and may have implications for both the course of the HIV infection and the epidemic.     

The CD160+ CD8high cytotoxic T cell subset correlates with response to HAART in HIV-1+ patients

We investigated the circulating cytotoxic CD160+ CD8(high) subset in correlation to antiviral immunity and response to highly active antiretroviral therapy (HAART) in HIV+ subjects. The study included 45 treatment-naive patients receiving HAART for 18 months, retrospectively defined as good (n=29) and transient (n=16) responders. HIV-specific CD8 T lymphocyte levels were measured by IFNgamma production in response to p17 Gag, in the presence of immobilized anti-CD160 mAb. We report a significantly increased baseline level of CD160+ CD8(high) subset in good therapy responders. CD160+ CD8(high) subset correlates with CD4+ T cell count, immune activation, and viral load. CD160+ CD8(high) lymphocytes contain a high amount of Granzyme B and include virus-specific T lymphocytes in HIV-1+ subjects. Co-stimulation through CD160 molecules enhances IFNgamma production in response to p17 Gag. Therefore, the CD160+ CD8(high) subset may be useful for monitoring of virus-specific cellular immunity and predicting response to antiretroviral therapy in chronic HIV-1 infection.     

Virologic Response to Tipranavir-Ritonavir or Darunavir-Ritonavir Based Regimens in Antiretroviral Therapy Experienced HIV-1 Patients: A Meta-Analysis and Meta-Regression of Randomized Controlled Clinical Trials

Background

The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.

Methods and Findings

A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61– 4.52) than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir). Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15 – 4.11). Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.

Conclusions

Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent viral load suppression effect as the duration of treatment is more prolonged.     

Hepatitis B and C Co-Infection in HIV Patients from the TREAT Asia HIV Observational Database: Analysis of Risk Factors and Survival

Background

We assessed the effects of hepatitis B (HBV) or hepatitis C (HCV) co-infection on outcomes of antiretroviral therapy (ART) in HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of HIV-infected patients in the Asia-Pacific region.

Methods

Patients testing HBs antigen (Ag) or HCV antibody (Ab) positive within enrollment into TAHOD were considered HBV or HCV co-infected. Factors associated with HBV and/or HCV co-infection were assessed by logistic regression models. Factors associated with post-ART HIV immunological response (CD4 change after six months) and virological response (HIV RNA <400 copies/ml after 12 months) were also determined. Survival was assessed by the Kaplan-Meier method and log rank test.

Results

A total of 7,455 subjects were recruited by December 2012. Of patients tested, 591/5656 (10.4%) were HBsAg positive, 794/5215 (15.2%) were HCVAb positive, and 88/4966 (1.8%) were positive for both markers. In multivariate analysis, HCV co-infection, age, route of HIV infection, baseline CD4 count, baseline HIV RNA, and HIV-1 subtype were associated with immunological recovery. Age, route of HIV infection, baseline CD4 count, baseline HIV RNA, ART regimen, prior ART and HIV-1 subtype, but not HBV or HCV co-infection, affected HIV RNA suppression. Risk factors affecting mortality included HCV co-infection, age, CDC stage, baseline CD4 count, baseline HIV RNA and prior mono/dual ART. Shortest survival was seen in subjects who were both HBV- and HCV-positive.

Conclusion

In this Asian cohort of HIV-infected patients, HCV co-infection, but not HBV co-infection, was associated with lower CD4 cell recovery after ART and increased mortality.     

Characterization of CD8 T-cell responses in HIV-1-exposed seronegative commercial sex workers from Nairobi, Kenya

CD8+ T-lymphocyte responses are crucial to the control of HIV-1; therefore, studying the CD8+ immune response in a naturally resistant population could provide valuable insights into an effective anti-HIV response in healthy uninfected individuals. Approximately 5-10% of the women in the Pumwani Commercial Sex Worker cohort in Nairobi, Kenya, have been highly exposed to HIV-1 yet remain HIV-IgG-seronegative and HIV-PCR negative (HIV(ES)). As IFN-gamma production correlates to cytotoxic function, the CD8+ T-lymphocyte IFN-gamma response to HIV p24 peptides was compared in HIV(ES) and HIV-infected (HIV+) individuals. Almost 40% of the HIV(ES) had a CD8+ IFN-gamma+ response that was five times lower in magnitude than that of the HIV+ group. The breadth of the response in HIV(ES) was very narrow and focused primarily on one peptide that is similar to the protective KK10 peptide. In the HIV+ group, low peripheral CD4+ counts negatively influenced the number of CD8+ cells producing IFN-gamma, which may undermine the ability to control HIV. Overall, many of the HIV(ES) women possess a HIV-1 p24-specific CD8+ IFN-gamma response, providing evidence to the specificity needed for an effective HIV vaccine.     

Protective Effect of HLA-B*5701 and HLA-C -35 Genetic Variants in HIV-Positive Caucasians from Northern Poland

Aim of the Study

Association of two HLA class I variants with HIV-1 pretreatment viremia, CD4+ T cell count at the care-entry and CD4+ T cell nadir.

Methods

414 HIV-positive Caucasians (30% women) aged 19-73 years were genotyped for HLA-C -35 (rs9264942) and HLA-B*5701 variants. HIV-1 viral load, as well as CD4+ T cell count at care-entry and nadir, were compared across alleles, genotypes and haplotypes.

Results

HLA-C -35 C/C genotype was found in 17.6% patients, C/T genotype in 48.1%, and T/T genotype in 34.3% patients. HLA-B*5701 variant was present in 5.8% of studied population. HIV plasma viremia in the group with C allele was significantly lower (p=0.0002) compared to T/T group [mean:4.66 log (SD:1.03) vs. 5.07 (SD:0.85) log HIV-RNA copies/ml, respectively], while CD4+ T cell count at baseline was notably higher among C allele carriers compared to T/T homozygotes [median: 318 (IQR:127-537) cells/μl vs. median: 203 (IQR:55-410) cells/μl, respectively] (p=0.0007). Moreover, CD4+ T cell nadir among patients with C allele [median: 205 (IQR:83.5-390) cells/μl] was significantly higher compared to T/T group [median: 133 (IQR:46-328) cells/μl] (p=0.006). Among cases with HLA-B*5701 allele, significantly lower pretreatment viremia and higher baseline CD4+ T cell count were found (mean: 4.08 [SD: 1.2] vs. mean: 4.84 [SD:0.97] log HIV-RNA copies/ml, p=0.003 and 431 vs. 270 cells/μl, p=0.04, respectively) compared to HLA-B*5701 negative individuals. The lowest viremia (mean: 3.85 log [SD:1.3]) HIV-RNA copies/ml and the highest baseline and nadir CD4+ T cell [median: 476 (IQR:304-682) vs. median: 361 (IQR: 205-574) cells/μl, respectively) were found in individuals with HLA-B*5701(+)/HLA-C –35 C/C haplotype.

Conclusions

HLA-C -35 C and HLA-B*5701 allele exert a favorable effect on the immunological (higher baseline and nadir CD4+ T cell count) and virologic (lower pretreatment HIV viral load) variables. This protective effect is additive for the compound HLA-B*5701(+)/HLA-C -35 C/C haplotype.     

Plasma Levels of Neopterin and C-Reactive Protein (CRP) in Tuberculosis (TB) with and without HIV Coinfection in Relation to CD4 Cell Count

Background

While the risk of TB is elevated in HIV-positive subjects with low CD4 cell counts, TB may in itself be associated with CD4 lymphocytopenia. We investigated markers of immune activation (neopterin) and inflammation (CRP) in TB patients with and without HIV coinfection and their association with CD4 cell levels, and determined their predictive capacity as alternative markers of advanced immunosuppression.

Methods

Participants selected from a cohort of adults with TB at Ethiopian health centers (195 HIV+/TB+, 170 HIV-/TB+) and 31 controls were tested for plasma levels of neopterin and CRP. Baseline levels of neopterin and CRP were correlated to CD4 cell count before and after anti-TB treatment (ATT). The performance to predict CD4 cell strata for both markers were investigated using receiver operating curves.

Results

Levels of both biomarkers were elevated in TB patients (neopterin: HIV+/TB+ 54 nmol/l, HIV-/TB+ 23 nmol/l, controls 3.8 nmol/l; CRP: HIV+/TB+ 36 μg/ml, HIV-/TB+ 33 μg/ml, controls 0.5 μg/ml). Neopterin levels were inversely correlated (-0.53, p<0.001) to CD4 cell count, whereas this correlation was weaker for CRP (-0.25, p<0.001). Neither of the markers had adequate predictive value for identification of subjects with CD4 cell count <100 cells/mm³ (area under the curve [AUC] 0.64 for neopterin, AUC 0.59 for CRP).

Conclusion

Neopterin levels were high in adults with TB, both with and without HIV coinfection, with inverse correlation to CD4 cell count. This suggests that immune activation may be involved in TB-related CD4 lymphocytopenia. However, neither neopterin nor CRP showed promise as alternative tests for immunosuppression in patients coinfected with HIV and TB.     

Altered EBV viral load setpoint after HIV seroconversion is in accordance with lack of predictive value of EBV load for the occurrence of AIDS-related non-Hodgkin lymphoma

In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8(+) T cells approximately 1 year before and 1 year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/10(6) PBMC (p < 0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827-2478 copies/10(6) PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8(+) T cells increased over HIV seroconversion (4.78 to 9.54/ micro l; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8(+) T cells tended to increase (from 12.2 to 17.31% CD27(-); p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8(+) T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphoma.     

Patterns of residual HIV-1 RNA shedding in the seminal plasma of patients on effective antiretroviral therapy

Background

More and more HIV-1-infected men on effective antiretroviral treatment (ART) have unprotected sex in order to procreate. The main factor influencing transmission is seminal HIV shedding. While the risk of HIV transmission is very low, it is difficult to assess in individuals. Nevertheless, it should be quantified.

Results

We retrospectively analysed seminal plasma HIV-1 shedding by 362 treated HIV-infected men attending a medically assisted reproduction centre (1998–2013) in order to determine its frequency, the impact of the antiretroviral regimen on HIV shedding, and to identify shedding patterns. The HIV-1 virus loads in 1396 synchronized blood and semen samples were measured, and antiretroviral treatment, biological and epidemiological data were recorded.We detected isolated HIV-1 shedding into the seminal plasma in 5.3% of patients on efficient antiretroviral treatment, but there was no association with the HIV antiretroviral drug regimen or the CD4 cell count. These men had undergone more regimen changes since treatment initiation and had been on the ongoing drug regimen longer than the non-shedding men. The patterns of HIV seminal shedding among patients with undetectable HIV blood virus load varied greatly. HIV seminal shedding can occur as long as 5 years after starting antiretroviral treatment.

Conclusions

The seminal HIV load was used to monitor risk for infertile HIV-infected patients on an assisted reproductive technology program. This can still be recommended for patients who recently (6 months) started ART, or those with a poor history of adherence to ART but may also be usefull for some patients during counselling. Residual HIV seminal shedding is probably linked to breaks in adherence to antiretroviral treatment but local genital factors cannot be ruled out.