Virological measures and factors associated with outcomes, and missing outcome data in HIV clinical trials: a methodological study

BackgroundTo evaluate the definition of HIV virological outcomes in the literature and factors associated with outcomes and missing outcome data.MethodsWe conducted a methodological review of HIV RCTs using a search (2009–2019) of PubMed, Embase and the Cochrane Central Register of Controlled Trials.Only full-text, peer-reviewed, randomised controlled trials (RCTs) that measured virological outcomes in people living with HIV, and published in English were included.We extracted study details and outcomes. We used logistic regression to identify factors associated with a viral threshold ≤50 copies/mL and linear regression to identify factors associated with missing outcome data.ResultsOur search yielded 5847 articles; 180 were included. A virological outcome was the primary outcome in 73.5% of studies. 89 studies (49.4%) used virological success. The remaining used change in viral load (VL) (33 studies, 18.3%); virological failure (59 studies, 32.8%); or virological rebound (9 studies, 5.0%). 96 studies (53.3%) set the threshold at ≤50 copies/mL; and 33.1% used multiple measures.Compared with government and privately funded studies, RCTs with industry funding (adjusted OR 6.39; 95% CI 2.15 to 19.00; p<0.01) were significantly associated with higher odds of using a VL threshold of ≤50 copies/mL. Publication year, intervention type, income level and number of patients were not associated with a threshold of ≤50 copies/mL. Trials with pharmacological interventions had less missing data (β=−11.04; 95% CI −20.02 to −1.87; p=0.02).DiscussionCountry source of funding was associated with VL threshold choice and studies with pharmacological interventions had less missing data, which may in part explain heterogeneous virological outcomes across studies. Multiple measures of VL were not associated with missing data. The development of formal guidelines on virological outcome reporting in RCTs is needed.

Virological outcome among HIV infected patients transferred from pediatric care to adult units in Madrid, Spain (1997–2017)

The aim of this transversal study was to describe the virological and immunological features of HIV-infected youths transferred from pediatric to adult care units since 1997 vs. the non-transferred patients from the Madrid Cohort of HIV-infected children and adolescents in Spain. We included 106 non-transferred and 184 transferred patients under clinical follow-up in 17 public hospitals in Madrid by the end of December 2017. Virological and immunological outcomes were compared in transferred vs. non-transferred patients. ART drug resistance mutations and HIV-variants were analyzed in all subjects with available resistance pol genotypes and/or genotypic resistance profiles. Among the study cohort, 133 (72.3%) of 184 transferred and 75 (70.7%) of 106 non-transferred patients had available resistance genotypes. Most (88.9%) of transferred had ART experience at sampling. A third (33.3%) had had a triple-class experience. Acquired drug resistance (ADR) prevalence was significantly higher in pretreated transferred than non-transferred patients (71.8% vs. 44%; p = 0.0009), mainly to NRTI (72.8% vs. 31.1%; p < 0.0001) and PI (29.1% vs. 12%; p = 0.0262). HIV-1 non-B variants were less frequent in transferred vs. non-transferred (6.9% vs. 32%; p < 0.0001). In conclusion, the frequent resistant genotypes found in transferred youths justifies the reinforcement of HIV resistance monitoring after the transition to avoid future therapeutic failures.

Rilpivirine in HIV-1-positive women initiating pregnancy: to switch or not to switch?

Background Safety data about rilpivirine use during pregnancy remain scarce, and rilpivirine plasma concentrations are reduced during second/third trimesters, with a potential risk of viral breakthroughs. Thus, French guidelines recommend switching to rilpivirine-free combinations (RFCs) during pregnancy. Objectives To describe the characteristics of women initiating pregnancy while on rilpivirine and to compare the outcomes for virologically suppressed subjects continuing rilpivirine until delivery versus switching to an RFC. Methods In the ANRS-EPF French Perinatal cohort, we included women on rilpivirine at conception in 2010–18. Pregnancy outcomes were compared between patients continuing versus interrupting rilpivirine. In women with documented viral suppression (&lt;50 copies/mL) before 14 weeks of gestation (WG) while on rilpivirine, we compared the probability of viral rebound (≥50 copies/mL) during pregnancy between subjects continuing rilpivirine versus those switching to RFC. Results Among 247 women included, 88.7% had viral suppression at the beginning of pregnancy. Overall, 184 women (74.5%) switched to an RFC (mostly PI/ritonavir-based regimens) at a median gestational age of 8.0 WG. Plasma HIV-1 RNA nearest delivery was &lt;50 copies/mL in 95.6% of women. Among 69 women with documented viral suppression before 14 WG, the risk of viral rebound was higher when switching to RFCs than when continuing rilpivirine (20.0% versus 0.0%, P = 0.046). Delivery outcomes were similar between groups (overall birth defects, 3.8/100 live births; pregnancy losses, 2.0%; preterm deliveries, 10.6%). No HIV transmission occurred. Conclusions In virologically suppressed women initiating pregnancy, continuing rilpivirine was associated with better virological outcome than changing regimen. We did not observe a higher risk of adverse pregnancy outcomes.

Factors Affecting Virological Outcome When First-Line Antiretroviral Therapy Is Reintroduced After Unplanned Interruption

There is no guideline concerning choice of antiretroviral therapy (ART) for HIV-infected patients after unplanned interruption. We conducted a retrospective cohort study of HIV-infected patients reintroduced to first-line ART after having unplanned interruption for at least 1 month. Viral load was evaluated at 6 to 18 months after the reintroduction. There were 100 patients included in our study, and 55 of them achieved virological success. History of single interruption (adjusted odds ratio [aOR] 5.51%, 95% confidence interval [CI] 1.82-16.68, P = .003) and CD4 count ≥200 cell/mm3 at the time of reintroduction (aOR 4.33, 95% CI 1.14-16.39, P = .031) increased likelihood to achieve virological success.

Virological outcome measures during analytical treatment interruptions in chronic HIV-1 infected patients

Background Analytical treatment interruptions (ATI) are essential in research on HIV cure. However, the heterogeneity of virological outcome measures used in different trials hinders the interpretation of the efficacy of different strategies. Methods A retrospective analysis of viral load (VL) evolution in 334 ATI episodes in chronic HIV-1 infected patients collected from 11 prospective studies. Quantitative [baseline VL, set point, delta set point, VL and delta VL at given weeks after ATI, peak VL, delta peak VL, and area under the rebound curve], and temporal parameters [time to rebound (TtR), set point, peak, and certain absolute and relative VL thresholds] were described. Pairwise correlations between parameters were analyzed, and potential confounding factors (sex, age, time of known HIV infection, time on ART, and immunological interventions) were evaluated. Results Set point was lower than baseline VL (median delta set point -0.26. p< 0.001). This difference was >1 log10 copies/mL in 13.9% of the cases. Median TtR was 2 weeks; no patients had undetectable VL at week 12. Median time to set point was 8 weeks: by week 12, 97.4% of the patients had reached the set point. TtR and baseline VL were correlated with most temporal and quantitative parameters. The variables independently associated with TtR were baseline VL and the use of immunological interventions. Conclusions TtR could be an optimal surrogate marker of response in HIV cure strategies. Our results underline the importance of taking into account baseline VL and other confounding factors in the design and interpretation of these studies.