Are current guidelines adapted for patient eligibility to PrEP? A case report.

BACKGROUND: Despite effective antiretroviral therapy developed over the last decade, HIV infection remains a major worldwide public health problem. Recently, a promising preventive treatment has been made available for HIV prophylaxis, PrEP for pre-ExPosure Prophylaxis. Indeed, it was shown to significantly reduce the risk of HIV infection in patients exposed to high risk of infection such as men having sex with men (MSM), heterosexuals and people who inject drugs. Several issues pertaining to PrEP remain uncertain including short and long-term adverse events, drug resistance, risk compensation and resurgence of other sexually transmitted infections. CASE PRESENTATION: We report a case of a 52-year-old MSM eligible for PrEP as he was exposed to a high risk of HIV infection, presented no clinical symptoms of HIV primary infection and was seronegative for HIV. PrEP therapy was then initiated with fixed association of emtricitabine-tenofovir disoproxil. One month later, HIV tests using two different assays were positive, despite perfect compliance reported by the patient and confirmed by plasma drug level. A retrospective search for plasma viral RNA in the blood sample before PrEP initiation turned out positive. Genotyping and treatment sensitivity performed on sample after one month of PrEP showed a virus resistance to lamivudine and emtricitabine. Similar cases in the literature and pivotal studies have reported HIV infections in patients initiating or undergoing PrEP. These patients where either infected but still seronegative, displaying no clinical symptoms upon enrollment, or became infected during PrEP. Reasons are mainly poor compliance to treatment, resistance to PrEP, and lack of diagnosis before PrEP. Guidelines advocate safe sex behavior before initiation, search for clinical signs of HIV primary infection and two different serologic tests performed with one-month interval. DISCUSSION AND CONCLUSIONS: Our patient newly HIV infected received PrEP as he was still seronegative. Current recommendations fail to screen recently HIV infected, but still seronegative patients who are initiating PrEP. This issue raises strong concerns regarding the lack of adequate selection for eligibility to PrEP and may contribute to exposing partners to HIV infection and select viral mutations. Infection risk could be minimized by search for plasma viral HIV RNA at pre-inclusion, at least for patients suspected of unsafe behaviors such as non-respect of the non-exposure period before PrEP initiation.

Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial.

BACKGROUND: In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm. METHODS: We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses. RESULTS: During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up. CONCLUSION: The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00454337.

Highlights from the 2014 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): from cART management to the end of the HIV pandemic.

The 2014 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) provided a forum for investigators to hear the latest research developments in the clinical management of HIV and HCV infections as well as HIV cure research. Combined anti-retroviral therapy (c-ART) has had a profound impact on the disease prognosis and transformed this infection into a chronic disease. However, HIV is able to persist within the infected host and the pandemic is still growing. The main 2014 ISHEID theme was, hence "Together for a world without HIV and AIDS". In this report we not only give details on this main topic but also summarize what has been discussed in the areas of HCV coinfection and present a short summary on currently emerging viral diseases.

Failure of combined antiretroviral therapy intensification with maraviroc and raltegravir in chronically HIV-1 infected patients to reduce the viral reservoir: the IntensHIV randomized trial.

BACKGROUND: Ongoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial. PATIENTS AND METHODS: We randomly assigned for 48 weeks 22 patients to continue their current first line regimen of Truvada® plus Kaletra® or intensify it with Maraviroc and Raltegravir. The primary objective was to obtain a 50% decrease in proviral HIV-1 DNA levels in lymphoid cells with intensification. Blood samples were drawn at W-2, W0, W2, W4, W12, W24 and W48. Plasma viremia, cellular proviral DNA and cellular RNA, 2-LTR circles and lymphocytes subsets were assayed using validated methods. Patients in the intensified group underwent a gut biopsy at baseline and W48 to measure proviral DNA levels. Statistical analysis used parametric and non-parametric tests. RESULTS: Ten patients in each arm completed the trial. The 2 populations were comparable at baseline. No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs). No change in the reservoir size was observed in gut proviral DNA in the intensified arm. In this group, no increase in 2-LTR circles was observed as early as 2 weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay. However, a decrease in CD8(+) T cells activation was observed at 24 and 48 weeks, as well as in PBMCs HIV-1 RNA levels. CONCLUSION: We conclude that the intensification of a Protease Inhibitor regimen with Maraviroc and Raltegravir does not impact the blood proviral DNA reservoir of HIV but can decrease the cell-associated HIV RNA, the CD8 activation and has a possible impact on rectal proviral HIV DNA in some patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT00935480.

Eliminating the HIV reservoir.

In the past few years, major advances have been achieved in understanding the nature and the maintenance mechanisms of the HIV reservoir. Although antiretroviral therapy works well in a majority of patients, it faces problems of compliance, resistance, toxicity, and cost. In most cases, the remaining HIV reservoir precluding antiretroviral cessation consists of a tiny cell pool that is long-lived and inaccessible to current therapies. New strategies are therefore needed to either purge or control this residual reservoir and finally stop antiretroviral drugs. Both ways leading to a functional or a sterilizing cure are currently pursued. Several molecules have been identified to achieve these goals and some of them have already entered clinical testing in humans. In this article, we review recent findings on the biology of HIV persistence and detail how HIV eradication trials should be designed in the near future.

Conference highlights of the 5th international workshop on HIV persistence during therapy, 6-9 December 2011, St. Maartin, West Indies.

The December 2011 5th International Workshop on HIV Persistence during Therapy addressed the issue of HIV persistence among 210 scientists from 10 countries involved in the study of HIV reservoirs and the search of an HIV cure. High quality abstracts were selected and discussed as oral or poster presentations. The aim of this review is to distribute the scientific highlights of this workshop outside the group as analyzed and represented by experts in retrovirology, immunology and clinical research.

Highlights from the 2012 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): from cART management to the search of an HIV cure.

The 2012 International Symposium on HIV and Emerging Infectious Diseases (ISHEID) provided a forum for investigators to hear the latest research developments in the clinical management of HIV and HCV infections as well as HIV-1 reservoirs and cure research. Combined anti-retroviral therapy (c-ART) has had a profound impact on the disease prognosis of individuals living with HIV-1 infection. However, although these anti-retroviral regimens are able to reduce plasma viremia to below the limits of detection for sustained periods of time, there is a rapid recrudescence in plasma viremia if treatment is interrupted. Therefore, despite this potent anti-retroviral suppression, HIV-1 is able to persist within the infected individual. The main 2012 ISHEID theme was, hence "searching for an HIV cure". In this report we not only give details on this main topic of the 2012 ISHEID but also summarize what has been discussed in the areas of HIV epidemiology, access to care, antiretroviral therapy management and recent progress in the therapy of HCV infection in patients with HIV.

Potential strategies for an HIV infection cure.

Despite long-term viral suppression with antiretroviral therapy (ART), HIV persists in reservoirs and sanctuary sites. Lifelong therapy is therefore necessary, leading to problems of compliance, toxicity, and cost. Over the last few years, important advances have been made in our understanding of the composition and the maintenance mechanisms of the HIV reservoir. Although complete viral eradication is currently out of reach, a growing number of scientists think that a "functional" cure is achievable. This situation would combine no disease progression, no virus transmission, and a life expectancy close to uninfected individuals in the absence of ART. At acute HIV infection, ART increases the frequency of sustained viremia control after its discontinuation, compared with the natural history of untreated disease. For patients at the chronic stage of HIV infection, ART alone is insufficient to clear viral reservoirs and new molecules intended to purge this reservoir or gene therapy approaches are warranted. This search for a cure needs innovation, audaciousness, and coordination. It also needs political, institutional, and private commitments for funding, which by now are severely lacking.

Rectal cell-associated HIV-1 RNA: a new marker ready for the clinic.

Gut-associated lymphoid tissue is a huge reservoir for HIV-1. Developing new strategies to target "residual" HIV-1 in patients on effective therapy brings the need for an evaluation of tissue reservoirs in the clinic. We measured cell-associated HIV-1 RNA and DNA in blood and rectal biopsies from 23 patients, including 14 with undetectable viremia on HAART, by using an adaptation of commercially available tests. Rectal cell HIV-1 RNA was detected in all viremic patients, with median levels of 4.90 log(10) copies/million CD4. Although plasma viremia was found at a median of 3 copies/mL in "aviremic" patients, rectal cell HIV-1 RNA was detected in 28.5% with median levels of 5.17 log(10) copies/million CD4. Consequently, we propose to use this marker in future clinical trials targeting "residual" HIV-1 in patients with viremia below the detection limit.

Statements from the 15th International Symposium on HIV and Emerging Infectious Diseases (ISHEID), Toulon, France, May 28-30, 2008.

In May 2008, 800 delegates from 64 countries met at the International Symposium on HIV and Emerging Infectious Diseases in France to discuss a list of hot topics in HIV and hepatitis viruses. This article summarizes the statements obtained from these discussions around a list of 10 of these topics: (a) antiretroviral treatment for naïve patients; (b) use of integrase inhibitors; (c) antiretrovirals in development; (d) management of lipid abnormalities; (e) hepatotoxicity of antiretroviral therapy; (f) management of hepatitis B in HIV patients; (g) management of acute hepatitis C in HIV patients; (h) outcome of HIV-HCV co-infected patients; (i) preexposure prophylaxis in HIV infection; and (j) the long road to a preventive HIV vaccine. For each topic, we reported the main data presented by speakers and summarized the results of the subsequent discussions.

Population pharmacokinetics of atazanavir in human immunodeficiency virus-infected patients.

The aim of this study was to determine the population pharmacokinetic (PK) parameters of atazanavir in adult human immunodeficiency virus-infected patients to build up a Bayesian strategy for dosage regimen individualization. This was an observational study of patients treated with the once-daily regimen atazanavir associated with 100 mg of ritonavir. Blood samples were drawn at steady state at various times ranging from 1 to 26 hours postdose. Atazanavir plasma concentrations were determined by a validated reverse-phase high-performance liquid chromatography method. PK analysis of the atazanavir population was performed using a nonlinear mixed-effects model (NONMEM version 6). One hundred eighty-seven patients were included in the study. The atazanavir doses prescribed were 300 mg (n = 169), 400 mg (n = 12), 200 mg (n = 1), and 150 mg (n = 5). The atazanavir population PK was described using a 1-compartment model with first-order absorption. Mean PK parameter estimations (95% confidence interval, coefficients of variation %) were as follows: oral clearance (CL) = 7.6 L/h (6.9-8.3; 34%), volume of distribution (V) = 80.8 L (67.4-94; 37%), and absorption constant rate (Ka) = 1.05 hours (0.01-2.09; 156%). The mean estimated half-life (T-half) was 7.5 hours (95% confidence interval: 7.2 -7.8 hours). The estimated T-half of atazanavir was in agreement with that previously reported of 8.6 and 8.8 hours. We observed a wide interpatient variability for the PK parameters, especially for Ka. This population approach allowed us to determine atazanavir PK parameters in human immunodeficiency virus-infected patients in a real-life context and to perform Bayesian analysis to predict Ctrough from samples collected at any moment during the dosing interval. This could therefore improve therapeutic drug monitoring interpretations and provide an interesting tool for correlation with virologic data.

Highlights from the 8th International Workshop on HIV Persistence during Therapy, 12-15 December 2017, Miami, FL, USA.

Over 4 days, more than 500 scientists involved in HIV persistence research shared their new unpublished data and designed future perspectives towards ART-free HIV remission. This 8th International Workshop on HIV Persistence followed the format of past conferences but further focused on encouraging participation of young investigators, especially through submission of oral and poster presentations. The topic of the workshop was HIV persistence. Consequently, issues of HIV reservoirs and HIV cure were also addressed. In this article, we report the discussions as closely as possible; however, all the workshop abstracts can be found online at www.viruseradication.com.

Highlights from the 20th International Symposium on HIV and Emerging Infectious Diseases (ISHEID) 16-18 May 2018, Marseille, France: from HIV and comorbidities to global health.

The 20th International Symposium on HIV and Emerging Infectious Diseases took place in Marseille, France. It had a refreshing European look with reinforced partnerships with the European AIDS Clinical Society and the British HIV Association and with international speakers and participants. Topics included HIV and global health, HIV and hepatitis cure, the microbiome and immunotherapies, clinical research and methodology, as well as chemsex, pre-exposure prophylaxis, sexually transmitted infections and emerging infectious diseases. Novel areas of research were also described, such as electronic technology in order to improve HIV management, and the expert patient.

Real-World Efficacy of Daclatasvir and Sofosbuvir, With and Without Ribavirin, in HIV/HCV Coinfected Patients With Advanced Liver Disease in a French Early Access Cohort.

BACKGROUND: Efficacious, well-tolerated, direct antiviral agents have drastically changed the prognosis of hepatitis C virus (HCV) disease, but real-world data for oral treatments are limited in key populations such as HIV/HCV coinfection with advanced liver disease. Daclatasvir (DCV) efficacy and safety was assessed in the French "Autorisation Temporaire d'Utilisation" (ATU) program, providing DCV ahead of market authorization to patients with advanced HCV disease without other treatment options. METHODS: This was a subanalysis of HIV/HCV coinfected ATU patients treated with DCV plus sofosbuvir (SOF). Recommended duration was 24 weeks; addition of ribavirin (RBV) and/or shorter treatment was at the physician's discretion. The primary efficacy analysis was sustained virologic response at posttreatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. RESULTS: The efficacy population (N = 407) was mostly cirrhotic (72%, of whom 18% were decompensated), HCV treatment-experienced (82%), and infected with genotypes 1 (69%), 3 (12%), or 4 (19%). Median CD4 was 555 cells/mm; 95% had HIV RNA <50 copies/mL. Most (74%) were treated for 24 weeks; 14% received RBV. SVR12 was 92% overall (95% confidence interval: 88.6% to 94.0%); 90% (86.4% to 93.2%) in patients with cirrhosis; 95% (88.9% to 97.5%) in patients without cirrhosis. SVR12 was consistent across HCV genotypes and antiretroviral regimens. Among 617 patients with safety data, 7 discontinued for an adverse event and 10 died. CONCLUSIONS: DCV+SOF±RBV achieved high SVR12 and was well tolerated in this large real-world cohort of HIV/HCV coinfected patients with advanced liver disease.

Highlights from the Seventh International Workshop on HIV Persistence during Therapy, 8-11 December 2015, Miami, Florida, USA.

Over 4 days, more than 270 scientists involved in HIV persistence research convened to share their data and discuss future avenues to control HIV without continuous antiretroviral therapy. This 7(th) International Workshop on HIV Persistence followed the format of the preceding conferences but more time was given for discussing abstracts submitted by the participants and selected by the Steering and Scientific Committees. The topic of the workshop is HIV persistence: consequently, issues of HIV reservoirs and HIV cure are also addressed. In this article we report as closely as possible what was discussed. However, owing to length constraints, not everything is reported here but all the Workshop abstracts can be found online (www.viruseradication.com).

Highlights from the 2016 International Symposium on HIV & Emerging Infectious Diseases (ISHEID): 25-27 May, Marseille, France.

For three days in May 2016, the International Symposium on HIV & Emerging Infectious Diseases gathered participants from all over the world around the theme 'Fighting deadly viruses'. HIV infection remained the main topic of the meeting but hepatitis, Ebola and Zika viruses as well as other emergent pathogens were also extensively covered. In this article we have tried to summarise what was presented during the plenary lectures, the two keynote lectures, and some of the work accepted for oral presentation. However, all abstracts can be found on the Journal of Virus Eradication website ( viruseradication.com/abstract.php).

Stavudine in the face of cross-resistance between HIV-1 nucleoside reverse transcriptase inhibitors: a review.

Despite the current availability of over 15 antiretroviral drugs, diminishing antiretroviral options due to drug cross-resistance constitute a real challenge beyond first-line therapy. Although stavudine (d4T) shares several resistance mutations with other drugs in its class -i.e. nucleoside analogue mutations (NAMs)- literature regarding the actual impact of NAMs on HIV-1 resistance to d4T is conflicting. Several studies conducted over the past few years have, however, shown that the frequency with which d4T selects NAMs is much lower than using zidovudine (AZT), particularly when combined with lamivudine (3TC). In the latter case, NAMs have been found in less than 5% of cases after more than 12 weeks of therapy. In vitro studies have also shown that the impact of d4T on phenotypic drug susceptibility is much lower than that of AZT, with similar genotypic profiles. Few clinical trials have attempted to define a clinically relevant cut-off for phenotypic resistance to d4T. The results of these trials differ considerably and are highly dependent on the studied population. Nonetheless, these data help to clarify the strategic use of d4T in antiretroviral therapy, and to determine the best sequencing options for nucleoside reverse transcriptase inhibitors.

Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial.

BACKGROUND: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. METHODS: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per µL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. FINDINGS: Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log10 per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. INTERPRETATION: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. FUNDING: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.