Switching virally suppressed, treatment-experienced patients to a raltegravir-containing regimen does not alter levels of HIV-1 DNA

Background

Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group.

Methods

14 ART experienced individuals with a suppressed viral load (<50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at ≥2 timepoints up to 48±6 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays.

Results

There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95% CI: −11.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/10⁶ PBMCs at baseline and the other had 34 copies/10⁶ PBMCs at week 51.

Conclusions

The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravir treatment initiation.     

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.     

Monitoring HIV Viral Load in Resource Limited Settings: Still a Matter of Debate?

Introduction

Consequences of lack of viral monitoring in predicting the effects of development of HIV drug resistance mutations during HAART in resource-limited settings (RLS) is still a matter of debate.

Design

To assess, among HIV+ patients receiving their first-line HAART, prevalence of virological failure and genotypic resistance mutations pattern in a Médécins Sans Frontières/Ministry of Health programme in Busia District (Kenya).

Methods

Patients with HAART treatment for ≥12 months were eligible for the study and those with HIV-RNA ≥5000 copies/ml underwent genotypic study. Total HIV-1 RNA from Dried Blood Spots was extracted using Nuclisens method.

Results

926 patients were included. Among 274 (29.6%) patients with detectable viral load, 55 (5.9%) experienced treatment failure (viral load >5.000 copies/ml); 61.8% were female and 10 (18.2%) had clinical failure. Median CD4 cell count was 116 cell/mm3 (IQR: 54–189). Median HIV-RNA was 32,000 copies/ml (IQR: 11000–68000). Eighteen out of 55 (33%) samples could be sequenced on PR and RT genes, with resistance associated mutations (RAMs) in 15 out of 18 samples (83%). Among patients carrying RAMs, 12/15 (81%) harboured RAMs associated to thymidine analogues (TAMs). All of them (100%) showed M184V resistance associated mutation to lamivudine as well as NNRTI''s RAMS.

Conclusions

Virological failure rate in resource-limited settings are similar to those observed in developed countries. Resistance mutation patterns were concordant with HAART received by failing patients. Long term detectable viral load confers greater probability of developing resistance and as a consequence, making difficult to find out a cost-effective subsequent treatment regimen.     

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

Background

Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients.

Methods and Findings

Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median −0.2 and −0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus −44 cells/mm³, p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood.

Conclusion

In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515827","term_id":"NCT00515827"}}NCT00515827 Please see later in the article for the Editors'' Summary     

Virological Efficacy in Cerebrospinal Fluid and Neurocognitive Status in Patients with Long-Term Monotherapy Based on Lopinavir/Ritonavir: An Exploratory Study

Background

Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited.

Methods

Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load <50 copies/mL. HIV-1 RNA in CSF was determined by HIV-1 SuperLow assay (lower limit of detection, 1 copy/mL). Neurocognitive functioning was assessed using a recommended battery of neuropsychological tests covering 7 areas. Neurocognitive impairment (NCI) was determined and also a global deficit score (GDS) for study comparisons.

Results

Seventeen patients on LPV/r-MT and 17 on LPV/r-ART were included. Fourteen (82.4%) patients on LPV/r-MT and 16 (94.1%) on LPV/r-ART had HIV-1 RNA <1 copy/mL in CSF (p = 0.601). NCI was observed in 7 patients on LPV/r-MT and in 10 on LPV/r-ART (41% vs 59%; p = 0.494). Mean (SD) GDS was 0.22 (0.20) in patients on LPV/r-MT and 0.47 (0.34) in those on LPV/r-ART (p = 0.012).

Conclusions

Suppression of HIV in CSF is similar in individuals with durable plasma HIV-1 RNA suppression who are receiving LPV/r-MT or LPV/r-ART for at least 96 weeks. Findings for HIV-1 replication in CSF and neurocognitive status indicate that this strategy seems to be safe for CNS functioning.     

Predictors of Raised Viral Load during Antiretroviral Therapy in Patients with and without Prior Antiretroviral Use: A Cross-Sectional Study

Objectives

In Lagos, Nigeria, Médecins Sans Frontières (MSF) and the Ministry of Health (MoH) commenced free antiretroviral treatment (ART) in a hospital-based clinic. We performed a cross-sectional study to compare factors associated with raised viral load between patients with (“experienced”) and without (“naïve”) prior antiretroviral (ARV) exposure at commencement of ART at the clinic. We also examined factors influencing ARV adherence in experienced patients prior to clinic entry.

Methods

We included adult patients receiving ART from MSF who answered a questionnaire about previous antiretroviral use. Multivariate logistic regression was used to estimate odds ratios (OR) for raised viral load (≥1000 copies/mL).

Results

1246 (96%) patients answered: 1075 (86%) reported no, and 171 (14%) some, prior ARV exposure. ARV-naïve patients were more immunosuppressed at baseline: 65% vs 37% (p<0.001) had CD4<200; 17% vs 9% (p = 0.013) were WHO stage 4. Proportionately more experienced than naïve patients had raised viral loads (20% vs 9%, p<0.001) on ART in the MSF/MoH clinic. Raised viral load was associated with prior ARV experience (adjusted OR = 3.74, 95%CI 2.09–6.70, p<0.001) and complete interruption of current ART (adjusted OR = 3.71, 95%CI 2.06–6.68, p<0.001). Higher CD4 at time of VL and a higher self-rated score of recent adherence were associated with lower OR of a raised viral load. Among experienced patients who missed pills before joining MSF/MoH, most common reasons were because ARVS were not affordable (58%) or available (33%), with raised viral load associated with being unsure how to take them (OR = 3.16, 95%CI 1.10–9.12, p = 0.033).

Conclusions

Patients previously exposed to ARVs had increased OR of raised viral load. The cost and availability of ARVs were common reasons for missing ARVs before joining the MSF/MoH clinic, and inadequate patient knowledge was associated with raised viral load.     

Effect of Genital Herpes on Cervicovaginal HIV Shedding in Women Co-Infected with HIV AND HSV-2 in Tanzania

Objectives

To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.

Design

Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.

Results

Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions (geometric means 1634 vs 3339 copies/ml, p = 0.03). In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (log₁₀ copies/mL) was closely associated with HIV PVL (β = 0.51 per log₁₀ copies/ml increase, 95%CI:0.41–0.60, p<0.001) and HSV shedding (β = 0.24 per log₁₀ copies/ml increase, 95% CI:0.16–0.32, p<0.001) but not the presence of herpetic lesions (β = −0.10, 95%CI:−0.28–0.08, p = 0.27).

Conclusions

HIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility.     

Effect of Natural and ARV-Induced Viral Suppression and Viral Breakthrough on Anti-HIV Antibody Proportion and Avidity in Patients with HIV-1 Subtype B Infection

Background

Viral suppression and viral breakthrough impact the humoral immune response to HIV infection. We evaluated the impact of viral suppression and viral breakthrough on results obtained with two cross-sectional HIV incidence assays.

Methods

All samples were collected from adults in the US who were HIV infected for >2 years. Samples were tested with the BED capture enzyme immunoassay (BED-CEIA) which measures the proportion of IgG that is HIV-specific, and with an antibody avidity assay based on the Genetic Systems 1/2+ O ELISA. We tested 281 samples: (1) 30 samples from 18 patients with natural control of HIV-1 infection known as elite controllers or suppressors (2) 72 samples from 18 adults on antiretroviral therapy (ART), with 1 sample before and 2–6 samples after ART initiation, and (3) 179 samples from 20 virally-suppressed adults who had evidence of viral breakthrough receiving ART (>400 copies/ml HIV RNA) and with subsequent viral suppression.

Results

For elite suppressors, 10/18 had BED-CEIA values <0.8 normalized optical density units (OD-n) and these values did not change significantly over time. For patients receiving ART, 14/18 had BED-CEIA values that decreased over time, with a median decrease of 0.42 OD-n (range 0.10 to 0.63)/time point receiving ART. Three patterns of BED-CEIA values were observed during viral breakthrough: (1) values that increased then returned to pre-breakthrough values when viral suppression was re-established, (2) values that increased after viral breakthrough, and (3) values that did not change with viral breakthrough.

Conclusions

Viral suppression and viral breakthrough were associated with changes in BED-CEIA values, reflecting changes in the proportion of HIV-specific IgG. These changes can result in misclassification of patients with long-term HIV infection as recently infected using the BED-CEIA, thereby influencing a falsely high value for cross-sectional incidence estimates.     

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background

Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

Methods and Findings

A5164 was a randomized strategy trial of “early ART” - given within 14 days of starting acute OI treatment versus “deferred ART” - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) ≥50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS.282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively.The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.

Conclusions

Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00055120","term_id":"NCT00055120"}}NCT00055120     

Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection

Objectives

The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).

Design

Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.

Methods

Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.

Results

Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48–51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL≥400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26–0.64) log₁₀ copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm³ was comparable to that experienced by PHI participants.

Conclusions

Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.     

Using Plasma Viral Load to Guide Antiretroviral Therapy Initiation to Prevent HIV-1 Transmission

Background

Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts ≤350 cells/µL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted.

Methods

Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts >350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: i) CD4 count <500 cells/µL, ii) viral load ≥10,000 or ≥50,000 copies/mL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions.

Results

Initiating treatment at viral load ≥50,000 copies/mL would require treating 19.8% of infected persons with CD4 counts >350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load ≥10,0000 copies/mL had a ratio of 1.5. In contrast, initiation at CD4 count <500 would require treating 41.8%, while averting 48.4% (ratio 1.1).

Conclusion

Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility.     

HIV-1 RNA May Decline More Slowly in Semen than in Blood following Initiation of Efavirenz-Based Antiretroviral Therapy

Objectives

Antiretroviral therapy (ART) decreases HIV-1 RNA levels in semen and reduces sexual transmission from HIV-1-infected men. Our objective was to study the time course and magnitude of seminal HIV-1 RNA decay after initiation of efavirenz-based ART among 13 antiretroviral-naïve Kenyan men.

Methods

HIV-1 RNA was quantified (lower limit of detection, 120 copies/mL) in blood and semen at baseline and over the first month of ART. Median log₁₀ HIV-1 RNA was compared at each time-point using Wilcoxon Signed Rank tests. Perelson’s two-phase viral decay model and nonlinear random effects were used to compare decay rates in blood and semen.

Results

Median baseline HIV-1 RNA was 4.40 log₁₀ copies/mL in blood (range, 3.20–5.08 log₁₀ copies/mL) and 3.69 log₁₀ copies/mL in semen (range, <2.08–4.90 log₁₀ copies/mL). The median reduction in HIV-1 RNA by day 28 was 1.90 log₁₀ copies/mL in blood (range, 0.56–2.68 log₁₀ copies/mL) and 1.36 log₁₀ copies/mL in semen (range, 0–2.66 log₁₀ copies/mL). ART led to a decrease from baseline by day 7 in blood and day 14 in semen (p = 0.005 and p = 0.006, respectively). The initial modeled decay rate was slower in semen than in blood (p = 0.06). There was no difference in second-phase decay rates between blood and semen.

Conclusions

Efavirenz-based ART reduced HIV-1 RNA levels more slowly in semen than in blood. Although this difference was of borderline significance in this small study, our observations suggest that there is suboptimal suppression of seminal HIV-1 RNA for some men in the early weeks of treatment.     

Antiretroviral Therapy Reduces HIV Transmission in Discordant Couples in Rural Yunnan,China

Background

Although HIV treatment as prevention (TasP) via early antiretroviral therapy (ART) has proven to reduce transmissions among HIV-serodiscordant couples, its full implementation in developing countries remains a challenge. In this study, we determine whether China''s current HIV treatment program prevents new HIV infections among discordant couples in rural China.

Methods

A prospective, longitudinal cohort study was conducted from June 2009 to March 2011, in rural Yunnan. A total of 1,618 HIV-discordant couples were eligible, 1,101 were enrolled, and 813 were followed for an average of 1.4 person-years (PY). Routine ART was prescribed to HIV-positive spouses according to eligibility (CD4<350 cells/µl). Seroconversion was used to determine HIV incidence.

Results

A total of 17 seroconversions were documented within 1,127 PY of follow-up, for an overall incidence of 1.5 per 100 PY. Epidemiological and genetic evidence confirmed that all 17 seroconverters were infected via marital secondary sexual transmission. Having an ART-experienced HIV-positive partner was associated with a lower rate of seroconvertion compared with having an ART-naïve HIV-positive partner (0.8 per 100 PY vs. 2.4 per 100 PY, HR = 0.34, 95%CI = 0.12–0.97, p = 0.0436). While we found that ART successfully suppressed plasma viral load to <400 copies/ml in the majority of cases (85.0% vs. 19.5%, p<0.0001 at baseline), we did document five seroconversions among ART-experienced subgroup.

Conclusions

ART is associated with a 66% reduction in HIV incidence among discordant couples in our sample, demonstrating the effectiveness of China''s HIV treatment program at preventing new infections, and providing support for earlier ART initiation and TasP implementation in this region.     

Ten Year Trends in Community HIV Viral Load in Barbados: Implications for Treatment as Prevention

Background

Treatment as prevention is a paradigm in HIV medicine which describes the public health benefit of antiretroviral therapy (ART). It is based on research showing substantial reductions in the risk of HIV transmission in persons with optimally suppressed HIV-1 Viral Loads (VL). The present study describes ten year VL trends at the national HIV treatment unit and estimates VL suppression at a population level in Barbados, a Caribbean island with a population of 277,000, an estimated adult HIV prevalence of 1.2%, and served by a single treatment unit.

Methods

The national HIV treatment centre of the Barbados Ministry of Health has a client VL database extending back to inception of the clinic in 2002 (n = 1,462 clients, n = 17,067 VL measurements). Optimal VL suppression was defined at a threshold value of ≤200 viral copies/mL.

Results

Analysis of VL trends showed a statistically significant improvement in VL suppression between 2002 to 2011, from 33.6% of clients achieving the 200 copies/mL threshold in 2002 to 70.3% in 2011 (P<0.001). Taking into account the proportion of clients alive and in care and on ART, the known diagnosed HIV population in Barbados, and estimates of unknown HIV infections, this translates into an estimated 26.2% VL suppression at a population level at the end of 2010.

Conclusions

We have demonstrated a significant trend towards optimal VL suppression in clients utilizing the services of the national HIV treatment program in Barbados over a 10-year period. Estimates of VL suppression at a population level are similar to reports in developed countries that applied similar methodologies and this could suggest a public health benefit of ART in minimizing the risk of sexual transmission of HIV. Continued efforts are warranted to extend HIV testing to hidden populations in Barbados and linking infected persons to care earlier in their disease.     

Cellular Levels of HIV Unspliced RNA from Patients on Combination Antiretroviral Therapy with Undetectable Plasma Viremia Predict the Therapy Outcome

Background

Combination antiretroviral therapy (cART), the standard of care for HIV-1 infection, is considered to be successful when plasma viremia remains below the detection limit of commercial assays. Yet, cART fails in a substantial proportion of patients after the apparent success. No laboratory markers are known that are predictive of cART outcome in initial responders during the period of undetectable plasma viremia.

Methodology/Principal Findings

Here, we report the results of a retrospective longitudinal study of twenty-six HIV-infected individuals who initially responded to cART by having plasma viremia suppressed to <50 copies/ml. Eleven of these patients remained virologically suppressed, whereas fifteen experienced subsequent cART failure. Using sensitive methods based on seminested real-time PCR, we measured the levels of HIV-1 proviral (pr) DNA, unspliced (us) RNA, and multiply spliced RNA in the peripheral blood mononuclear cells (PBMC) of these patients at multiple time points during the period of undetectable plasma viremia on cART. Median under-therapy level of usRNA was significantly higher (0.43 log₁₀ difference, P = 0.0015) in patients who experienced subsequent cART failure than in successfully treated patients. In multivariate analysis, adjusted for baseline CD4⁺ counts, prior ART experience, and particular cART regimens, the maximal usRNA level under therapy was the best independent predictor of subsequent therapy failure (adjusted odds ratio [95% CI], 24.4 [1.5–389.5], P = 0.024). The only other factor significantly associated with cART failure was prior ART experience (adjusted odds ratio [95% CI], 12.3 [1.1–138.4], P = 0.042). Levels of usRNA under cART inversely correlated with baseline CD4⁺ counts (P = 0.0003), but did not correlate with either baseline usRNA levels or levels of prDNA under therapy.

Conclusion

Our data demonstrate that the level of HIV-1 usRNA in PBMC, measured in cART-treated patients with undetectable plasma viremia, is a strong predictive marker for the outcome of therapy.     

Medication Possession Ratio Associated with Short-Term Virologic Response in Individuals Initiating Antiretroviral Therapy in Namibia

The visual-analogue scale (VAS), Likert item (rating scale), pills identification test (PIT), and medication possession ratio (MPR) provide estimates of antiretroviral therapy (ART) adherence which correlate with HIV viral suppression. These simple adherence measures are inexpensive and easy to administer; however, require validation and adjustment prior to implementation. The objective of this study was to define the optimal adherence assessment measure in Namibia to identify patients at risk for sub-optimal adherence and poor virologic response 6 months after ART initiation. We conducted a cross-sectional survey in HIV-infected adults receiving ART for 6–12 months prior to the adherence assessment. Adherence measures included 30-day VAS, 30-day Likert item, self-reported treatment interruptions, PIT, and MPR. Association of adherence measures with 6-month HIV-1 RNA level was assessed using two thresholds (1000 copies/mL and 5000 copies/mL). Adherence was assessed in 236 patients, mean age 37.3 years, 54% female. Mean adherence was 98.1% by 30-day VAS, 84.7% by 30-day Likert item, 97.0% by self-reported treatment interruptions, 90.6% by PIT, and 98.8% by MPR. Agreement between adherence measures was poor using kappa statistic. 76% had HIV-1 RNA <1000 copies/ml, and 88% had HIV-1 RNA <5000 copies/ml. MPR (continuous) was associated with viral suppression <5000 copies/ml (p = 0.036). MPR <75% was associated with virologic failure at ≥5000 copies/ml with OR 3.89 (1.24, 12.21), p = 0.013. Adherence was high with all measures. Only MPR, was associated with short-term virologic response, suggesting its cross-culturally utility for early identification of patients at high risk for virologic failure.     

Three Generic Nevirapine-Based Antiretroviral Treatments in Chinese HIV/AIDS Patients: Multicentric Observation Cohort

Background

The purpose of this study was to evaluate the efficacy and safety of three nevirapine-based antiretroviral treatments for adult antiretroviral-naïve Chinese patients with HIV-1 infection.

Methodology

This was a prospective, multicenter study. 198 antiretroviral-naïve HIV-1 positive subjects with CD4 lymphocyte counts between 100/ul and 350/ul and plasma HIV-1 RNA levels more than 500 copies/ml were randomized to start three NVP-based antiretroviral treatments: group A, NVP+AZT+ddI; group B, NVP+3TC+d4T; group C, NVP+AZT+3TC. Viral responses, immunologic responses, adverse events and drug resistence were monitored at baseline and the end of week 4, 12, 24, 36, 52. Viralogical response and immunological response were also comparaed in different strata of baseline CD4 T lymphocyte counts and plasma HIV-1 RNA concentrations. At baseline, the plasma HIV-1 RNA was 4.44±0.68, 4.52±0.71 and 4.41±0.63 lg copies/ml in group A, B and C respectively (p = 0.628). At the end of the study, the plasma viral load reached 2.54±1.11, 1.89±0.46 and 1.92±0.58 lg copies/ml in group A, B and C respectively (p<0.001). At week 52, suppression of plasma HIV-1 RNA to less than 50 copies/ml was achieved in more patients in group B and C than in group A (68.2%, 69% vs. 39.7%; p<0.001). In planned subgroup analyses, the decrease of viral response rate was seen in group A when CD4 cell count >200/ul (subgroup H). But in subgroup L, viral response rate of three groups has no significant statistic difference. There were no statistically significant differences among three groups in immunological response wthin any of the CD4 or pVL strata. 3 out of 193 patients with available genotype at baseline showed primary drug resistant. Of 26 patients with virologic failure, 17 patients showed secondary drug resistant, 16 subjects in group A and 1 subject in group B. Logistic regression analysis indicated that presence of hepatotoxicity was associated with HCV-Ab positive (OR = 2.096, 95%CI: 1.106–3.973, P = 0.023) and higher CD4 baseline (CD4 count >250/ul)(OR = 2.096, 95%CI: 1.07–4.107, P = 0.031).

Conclusion

Our findings strongly support the use of 3TC+d4T and 3TC+AZT as the nucleoside analogue combination in NVP-based antiretroviral therapy. The regimen of AZT+ddI+NVP produced poor virological response especially in the stratum of CD4 count more than 200/ul. More patients showed secondary drug resistant in this arm too. Patients with HCV-Ab+ and CD4 count >250/ul appear to have significantly high risk of hepatoxicity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00618176","term_id":"NCT00618176"}}NCT00618176