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Despite highly active antiretroviral therapy, active replication persists and drives immune activation in some individuals with HIV. This activation is higher if therapy is intensified by additional antiretroviral drugs ( pages 373–374 ). Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted 1 , 2 . Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels 3 , suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs 4 , 5 . Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Background. It is unknown if tenofovir disoproxil fumarate (TDF), which is often coformulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect. Methods. We performed a randomized, crossover, double-blind, placebo-controlled clinical trial on human immunodeficiency virus type 1 (HIV-1)–infected subjects with HIV-1 RNA < 50 copies/mL during ≥6 months on stable darunavir/ritonavir (800/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily) monotherapy, fasting total cholesterol (TC) ≥200 mg/dL or low-density lipoprotein cholesterol (LDL-c) ≥130 mg/dL, and no lipid-lowering drugs. In arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (washout) and 12 additional weeks of placebo (placebo period). Subjects in arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (washout). The primary endpoint was change in median fasting TC levels. Results. Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced TC from 234 to 205 mg/dL (P < .001), LDL-c from 155 to 128 mg/dL (P < .001), and high-density lipoprotein cholesterol (HDL-c) from 50.3 to 44.5 mg/dL (P < .001). It also decreased the proportion of subjects with fasting TC ≥200 mg/dL from 86.7% to 56.8% (P = .001), and LDL-c ≥130 mg/dL from 87.8% to 43.9% (P < .001). After 12 weeks, TDF/FTC exposure was associated with lower TC and LDL-c levels than placebo (P = .001 and P = .002, respectively). The TC/HDL-c ratio and triglyceride levels did not change with TDF/FTC exposure. Conclusions. Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF. Clinical Trials Registration. NCT01458977.

Inflammatory biomarkers may be impacted by smoking, obesity, type 2 diabetes, chronic obstructive lung disease, hazardous alcohol consumption, active chronic hepatitis, illicit drug use, depression, menopause, and other lifestyle factors (5). [...]many putative drivers of inflammatory state in PLWH may not be corrected with plasma HIV suppression and may be independent of the chosen antiretrovirals. [...]a similar CD4/CD8 ratio recovery has been reported after initiation of a 2DR (dolutegravir plus lamivudine) versus dolutegravir- or bictegravir-based 3DR in naive PLWH (6). [...]a strong correlation between biomarkers impacted by the same condition, namely, IL-6, sCD14, hs-CRP, and D-dimer, has generally been shown in most cohort studies, and all of them were predictors of AIDS, serious non-AIDS events, mortality, and a broad array of morbidities (5,15–18). [...]Serrano-Villar et al. considered that it would be important to analyze the impact of these differences on the risk of clinical events in very large studies. In summary, there is compelling evidence that dolutegravir/lamivudine or dolutegravir/rilpivirine has a comparable impact on inflammatory and atherogenesis biomarkers versus 3DRs in their pivotal randomized controlled trials.

The objective of this analysis is to perform an indirect comparison of elvitegravir, cobicistat, emtricitabine and tenofovir DF (E/C/F/TDF) to abacavir/lamivudine and dolutegravir (ABC/3TC + DTG) by using 2 trials evaluating each of these regimens in comparison to efavirenz, emtricitabine and tenofovir DF (EFV/FTC/TDF). An indirect comparison was performed by using a generalization of Bucher's methodology to calculate risk differences. Two phase III clinical trials (GS-US-236-0102 and SINGLE-described above) were used. Results of the indirect comparison showed no statistically significant risk difference of the efficacy endpoint of achieving HIV RNA < 50 copies/mL between E/C/F/TDF and ABC/3TC + DTG for the ITT population at weeks 48, 96 and 144: respectively -3.7% (CI95% = [-10.8%; 3.4%]), -5.2% (CI95% = [-13.2%; 2.8%]) and -3.1% (CI95% = [-12.0%; 5.7%]). There was no statistically significant differences in the risk difference for serious adverse events (5.7% (CI95% = [-2.2%; 12.3%])), drug related adverse event (2.7% (CI95% = [-7.0%;12.4%])), drug related serious adverse event (0.8% (CI95% = [-1.6%;3.2%])) and death (0.5% (CI95% = [-0.8%;1.8%])), respectively, between E/C/F/TDF and ABC/3TC + DTG. A significant difference was found for discontinuation due to adverse events with a higher rate for E/C/F/TDF (difference = 8.6% (CI95% = [3.3%; 13.9%])). There was also no statistically significant risk difference of the viral resistance of 1.2% (CI95% = [-1.2; 3.7]) between E/C/F/TDF and ABC/3TC + DTG at week 48, 1.7% at week 96 (CI95% = [-1.1; 4.5]) and 2.2% (CI95% = [-1.0; 5.4]) at week 144.

To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/μL. Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04). In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.

Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm , exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm at any time during 48-week analysis periods through week 192. Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm , 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm at any time vs those sustaining <200 cells/mm . No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm . Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

BackgroundInterferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART).MethodsPersons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay.ResultsIP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH≥ 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels.ConclusionPlasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels.

Virological suppression rates achieved with the new antiretroviral drugs in patients with virological failure and resistance to multiple drug classes are nearly matching the rates seen in treatment-naive patients. Knowledge of cross-resistance patterns to drugs of the same class is key for successful use of etravirine, tipranavir, and darunavir in treatment-experienced patients. Determination of human immunodeficiency virus type 1 (HIV-1) tropism is cardinal for maraviroc. The impressive potency of raltegravir must not preclude its use with other active drugs because of its limited genetic barrier. These new agents have demonstrated superiority in virtually all efficacy parameters in their pivotal salvage trials, but comparative data between them are still very scarce. This review discusses the clinical implication of resistance to these new drugs. Specific genotypic resistance scores have been developed for tipranavir and etravirine, and mutations conferring resistance to darunavir are well understood. Determining the most active drugs and successfully combining them is the key challenge in salvage regimens.

In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0.042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P<10(-6) AMOVA test; P = 0.001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P<10(-6)) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infection.

Background Schistosomiasis is highly endemic in sub-Saharan Africa and frequently imported to Europe. Male urogenital manifestations are often neglected. We aimed to ascertain the prevalence of genitourinary clinical signs and symptoms among long-term African migrants in a non-endemic European country using a serology test. Methods We carried out a prospective, community-based cross-sectional study of adult male migrants from sub-Saharan Africa living in Spain. Schistosoma serology tests and microscopic urine examinations were carried out, and clinical data were obtained from an electronic medical record search and a structured questionnaire. Results We included 388 adult males, mean age 43.5 years [Standard Deviation ( SD)  = 12.0, range: 18–76]. The median time since migration to the European Union was 17 [Interquartile range (IQR): 11–21] years. The most frequent country of origin was Senegal ( N  = 179, 46.1%). Of the 338, 147 (37.6%) tested positive for Schistosoma. Parasite eggs were present in the urine of only 1.3%. Nine genitourinary clinical items were significantly associated with positive Schistosoma serology results: pelvic pain (45.2%; OR  = 1.57, 95% CI : 1.0–2.4), pain on ejaculation (14.5%; OR  = 1.85, 95% CI : 1.0–3.5), dyspareunia (12.4%; OR  = 2.45, 95% CI : 1.2–5.2), erectile dysfunction (9.5%; OR  = 3.10, 95% CI : 1.3–7.6), self-reported episodes of infertility (32.1%; OR  = 1.69, 95% CI : 1.0–2.8), haematuria (55.2%; OR  = 2.37, 95% CI : 1.5–3.6), dysuria (52.1%; OR  = 2.01, 95% CI : 1.3–3.1), undiagnosed syndromic STIs (5.4%), and orchitis (20.7%; OR  = 1.81, 95% CI : 1.0–3.1). Clinical signs tended to cluster. Conclusions Urogenital clinical signs and symptoms are prevalent among male African long-term migrants with a positive Schistosoma serology results. Genital involvement can be frequent even among those with long periods of non-residence in their sub-Saharan African countries of origin. Further research is needed to develop diagnostic tools and validate therapeutic approaches to chronic schistosomiasis. Graphical Abstract