Antiretroviral Therapy Re-initiation Research Articles

Evaluation of a Public Health Referral System to Re-Engage Individuals Living With HIV Who Have Interrupted Antiretroviral Therapy in British Columbia, Canada.

In 2016, the British Columbia HIV/AIDS Drug Treatment Program modified its prescriber alert system for antiretroviral therapy (ART) interruptions to include referrals to regional public health nursing teams for direct outreach support for those who remain off treatment for 4 months or longer. We evaluated clinically relevant outcomes of this Re-Engagement and Engagement in Treatment for Antiretroviral Interrupted and Naïve populations (RETAIN) initiative, in comparison to previous time-periods. We analyzed ART interruptions triggering alerts in pre-RETAIN (July 2013-April 2016) and post-RETAIN periods (May 2016-October 2017) with follow-up continuing until October 2018. We compared the proportions of those who restarted ART and achieved viral suppression in pre-RETAIN and post-RETAIN periods and the time to ART restart using generalized estimating equations. Cox proportional hazards modelling was used to examine associations with time-to-ART-restart. A total of 1805 individuals experienced ART interruptions triggering 3219 alerts; 2050 in pre-RETAIN and 1169 in post-RETAIN periods. Participants were predominantly men (74%) and had a median duration of ART of 5 years. Among persons who remained interrupted >4 months after an ART interruption alert was sent, the median time from interruption to ART re-initiation declined from 8.7 months to 7.4 months (P < 0.001) from pre-to post-RETAIN periods. Interruptions in the post-RETAIN era were associated with an increased hazard of restarting ART (adjusted hazard ratio 1.51; 95% CI: 1.34 to 1.69). Public health referrals shortened the length of ART interruptions after alerts sent to prescribers had not resulted in re-engagement. Similar programs should be considered in other jurisdictions.

Effectiveness of an HIV care model integrated into addiction care based on medication-assisted treatment for HIV-positive people who use drugs

ABSTRACT Our objective was to evaluate the effectiveness of initiated or reinitiated antiretroviral therapy (ART) in HIV-positive active drug users receiving integrated HIV and addiction care in a harm reduction setting. We performed a study of HIV-positive persons who use drugs (PWUD) in a harm reduction unit in Madrid, Spain. Participants received HIV care integrated into addiction care and received at least one dose of observed ART based on medication-assisted treatment between January 2013 and December 2019. Individuals newly diagnosed with HIV (n = 13) had a greater median CD4 cell count at baseline were less likely to be late presenters, had a greater CD4 cell count increase, and were less likely to have AIDS in comparison to those who were aware of their HIV status (n = 87) at initiation or reinitiation of ART. The overall VS was 73% in the intention-to-treat (ITT) analysis and 92.4% in the modified intention-to-treat (mITT) analysis. People who were engaged in OST, people with >90% adherence to ART, and older people were positively associated with VS in the multivariate analysis. An HIV care model integrated into a harm reduction facility demonstrated a high uptake of HIV treatment, retention in care, improvement in adherence, and achievement of VS.

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity

IntroductionContinuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of...

A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection

Objective and DesignA randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI). MethodsFifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI. ResultsFifteen participants on ART (median: 178 weeks: range 79–295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation. ConclusionsAdministration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.

Factors Associated With Antiretroviral Therapy Reinitiation in Medicaid Recipients With Human Immunodeficiency Virus.

This study was conducted to examine patient characteristics associated with antiretroviral therapy (ART) reinitiation in Medicaid enrollees. This is a retrospective cohort study that uses Cox proportional hazard regression to examine the association between person-level characteristics and time from ART discontinuation to the subsequent reinitiation within 18 months. There were 45 409 patients who discontinued ART, and 44% failed to reinitiate. More outpatient visits (3+ vs 0 outpatient visits: adjusted hazard ratio (adjHR), 1.56; 99% confidence interval [CI], 1.45-1.67) and hospitalization (adjHR, 1.18; 99% CI,1.16-1.20) during follow-up were associated with reinitiation. Failure to reinitiate ART within 18 months was common in this sample. Care engagement was associated with greater ART reinitiation.

Combined estimation of disease progression and retention on antiretroviral therapy among treated individuals with HIV in the USA: a modelling study

Accurately estimating HIV disease progression and retention on antiretroviral therapy (ART) can help inform interventions to control HIV microepidemics and mathematical models used to inform health-resource allocation decisions. Our objective was to estimate the monthly probabilities of on-ART CD4 T-cell count progression, mortality, ART dropout, and ART reinitiation using a continuous-time multistate Markov model. We also aimed to validate health-state transition probability estimates to ensure they accurately reproduced the regional HIV microepidemics across the USA. In our modelling study, we considered a cohort of patients from the HIV Research Network, a consortium of 17 adult and paediatric HIV-care providers located in the northeastern (n=8), southern (n=5), and western (n=4) regions of the USA. Individuals aged 15 years or older who were in HIV care (defined as one CD4 test and one HIV-care visit in a calendar year period) with at least one ART prescription between Jan 1, 2010, and Dec 31, 2015, were included in the analysis. We used continuous-time multistate Markov models to estimate transitions between CD4 strata and between on-ART and off-ART states. We examined and adjusted for differences in probability of transition by region, race or ethnicity, sex, HIV risk group, and other baseline clinical indicators. The median age of the 32 242 individuals included in the analysis was 44 years (interquartile range 35-51). Over a median follow-up of 4·9 years (2·6-6·0), 8614 (26·7%) of 32 242 people interrupted ART and 1325 (4·1%) of 32 242 people died. Women, men who have sex with men, and individuals with no previous ART experience had greater increases in CD4 cell counts, whereas black people and people who inject drugs had increased probabilities of ART dropout and faster disease progression. Regardless of CD4 strata, individuals had increased hazard for ART dropout if they were from the south (adjusted hazard ratio [aHR] range from 1·91, 95% CI 1·71-2·13, to 2·45, 2·29-2·62) or the west (aHR range from 1·29, 1·10-1·51, to 1·66, 1·51-1·82) of the USA, compared with individuals from the northeast USA. Our results show heterogeneities in disease progression during ART and probability of ART retention across race and ethnicity, HIV risk groups, and regions. These differences should be viewed as targets for intervention and should be incorporated in mathematical models of regional HIV microepidemics in the USA. US National Institutes of Health, Agency for Healthcare Research and Quality, and Health Resources and Services Administration.

Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection.

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)-infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals.

Therapeutic strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission in infected individuals are under active investigation. Considering the vast majority of HIV-infected individuals experience plasma viral rebound upon cessation of therapy, clinical trials evaluating the efficacy of curative strategies would likely require inclusion of ART interruption. However, it is unclear what impact short-term analytical treatment interruption (ATI) and subsequent reinitiation of ART have on immunologic and virologic parameters of HIV-infected individuals. Here, we show a significant increase of HIV burden in the CD4+ T cells of infected individuals during ATI that was correlated with the level of plasma viral rebound. However, the size of the HIV reservoirs as well as immune parameters, including markers of exhaustion and activation, returned to pre-ATI levels 6–12 months after the study participants resumed ART. Of note, the proportions of near full-length, genome-intact and structurally defective HIV proviral DNA sequences were similar prior to ATI and following reinitiation of ART. In addition, there was no evidence of emergence of antiretroviral drug resistance mutations within intact HIV proviral DNA sequences following reinitiation of ART. These data demonstrate that short-term ATI does not necessarily lead to expansion of the persistent HIV reservoir nor irreparable damages to the immune system in the peripheral blood, warranting the inclusion of ATI in future clinical trials evaluating curative strategies.

HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis

SummaryBackgroundPretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs.MethodsThis study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions.FindingsWe identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5–15·9) in southern Africa, 10·1% (5·1–19·4) in eastern Africa, 7·2% (2·9–16·5) in western and central Africa, and 9·4% (6·6–13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16–29) in southern Africa, 17% (5–30) in eastern Africa, 17% (6–29) in western and central Africa, 11% (5–18) in Latin America and the Caribbean, and 11% (2–20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa.InterpretationPretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition.FundingBill & Melinda Gates Foundation and World Health Organization.

Impact of long-term antiretroviral therapy interruption and resumption on viral reservoir in HIV-1 infected patients.

: We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV-1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation. These data suggest that the increase in reservoir after long-term ART discontinuation might not be reversible at midterm.

Hemorrhagic Stroke in an Adolescent Female with HIV-Associated Thrombotic Thrombocytopenic Purpura.

HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression.

Dropout and re-enrollment

EMOD-HIV v0.8 has been used to estimate the potential impact of expanding treatment guidelines to allow earlier initiation of antiretroviral therapy (ART) in sub-Saharan Africa with current or improved treatment coverage. In generating these results, a model must additionally make assumptions about the rates of dropout and re-initiation into ART programs before and after the program change, about which little is known. The objective of this work is to rigorously analyze modeling assumptions and the sensitivity of model results with respect to relevant mechanisms and parameters. We varied key model assumptions pertaining to ART dropout and re-enrollment to analyze their effect on the cost, impact, and cost-effectiveness of expanding treatment guidelines, and of expanding coverage via improved testing and linkage to care. Additionally, we performed a sensitivity analysis of 17 relevant model parameters. South Africa. Allowing re-initiation of ART irrespective of prior treatment doubled the cost and impact of expanding treatment guidelines, as compared with a scenario in which re-initiation could only be triggered by a health event (AIDS symptoms, diagnosis of a partner, or an antenatal care visit). Increasing the probability of 'voluntary' re-initiation (not triggered by a health event) was the most cost-effective way to improve the treatment program, especially in the short term because it provided immediate benefits to those who would otherwise have delayed re-initiation until the onset of AIDS symptoms. However, the maximum impact of this change was limited compared with expanding coverage through improvements in testing and linkage to care. Beyond improvements in coverage and re-initiation, further gains could be made by improving retention in care. Only with optimal retention in care was expansion of guidelines cost-saving after 20 years due to reductions in transmission. Re-initiation did not reduce transmission sufficiently to make a guideline change cost-effective due to transmission that occurred while patients were away from care. Sensitivity analysis suggested that enormous health benefits could be attained by improving treatment regimens to have higher efficacy at preventing transmission, increasing the proportion of the population with access to improved healthcare, and reducing 'leaks' in the 'cascade of care.' Increasing the proportion of individuals who receive CD4 cell results was particularly cost-effective at baseline levels of coverage, and increasing retention on ART was particularly cost-effective with expanded coverage. This analysis provides a sense of the magnitude of uncertainty in program cost and impact that policy-makers could anticipate in the face of uncertain future programmatic changes. Our findings suggest that increasing re-initiation is the most cost-effective means of initial program improvement, especially in the short term, but that improvements in retention are necessary in order to reap the full transmission-blocking benefits of a test-and-treat program in the long term.

Characterization of associations and development of atazanavir resistance after unplanned treatment interruptions

Although current guidelines recommend resistance testing prior to antiretroviral therapy (ART) reinitiation after treatment interruptions, virological failure of first-line ritonavir-boosted, protease-inhibitor (PI/r)-containing ART is associated with low emergent PI resistance. In patients experiencing unscheduled treatment interruptions (UTrIs) on ritonavir-boosted atazanavir (ATV/r) ART regimens, we hypothesized low emergence of PI mutations conferring resistance to ATV/r. In a retrospective assessment of HIV-infected patients initiating ATV/r-containing ART, using logistic regression we determined factors associated with UTrI, the prevalence of emergent resistance mutations and virological response after ART reinitiation. A total of 202 patients [median age 33 years (interquartile range (IQR) 29-40 years); 52% female; median CD4 count 184 cells/μL (IQR 107-280 cells/μL); median HIV RNA 4.6 log10 HIV-1 RNA copies/mL (IQR 3.2-5.1 copies/mL)] initiated ATV/r between 2004 and 2009; 80 (43%) were ART naïve. One hundred and ten patients (55%) underwent 195 UTrIs after a median (IQR) 25 (10-52) weeks on ART, with a median (IQR) UTrI duration of 10 (3-31) weeks. Fifty-four of 110 patients (49%) underwent more than one UTrI. The commonest reasons for UTrI were nonadherence (52.7%) and drug intolerance (20%). Baseline HIV RNA > 100 000 copies\mL [odds ratio (OR) 3.6; 95% confidence interval (CI) 1.3-9.95] and being HCV positive, an injecting drug user or on methadone (OR 2.4; 95% CI 1.3-4.4) were independently associated with UTrI. In 39 patients with at least two resistance assays during UTrIs, 72 new mutations emerged; four nucleoside reverse transcriptase inhibitor (NRTI), two nonnucleoside reverse transcriptase inhibitor (NNRTI) and 66 protease inhibitor (PI) resistance mutations. All emergent PI resistance mutations were minor mutations. At least 65% of patients were re-suppressed on ATV/r reinitiation. In this PI-treated cohort, UTrIs are common. All emergent PI resistance mutations were minor and ATV/r retained activity and efficacy when reintroduced, even after several UTrIs, raising questions regarding the need for routine genotypic resistance assays in PI/r-treated patients prior to ART reinitiation after UTrI.

Platelet count kinetics following interruption of antiretroviral treatment

To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. SMART patients from sites that determined platelets routinely. Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: -24 000/μl (-54 000 to 4000) vs. 3000 (-22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/μl) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2-2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = -0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.

Short-Term and Long-Term Clinical and Immunological Consequences of Stopping Antiretroviral Therapy in HIV-Infected Patients with Preserved Immune Function

The aim of this study was to assess the short-term and long-term consequences of stopping antiretroviral therapy (ART) in patients with preserved immune function. This was a randomized 144-week follow-up CD4⁺ T-cell-count-guided treatment-interruption trial. HIV-1-infected adults with plasma HIV-1 RNA<50 copies/ml, CD4⁺ T-cell count >500 cells/μl and nadir CD4⁺ T-cell count >100 cells/μl were randomized to continuous treatment (CT) or treatment interruption (TI) until CD4⁺ T-cell count decreased to <350 cells/μl. The primary end points were AIDS-defining illnesses, death, CD4⁺ T-cell count <200 cells/μl, or virological failure after restarting ART. A total of 106 patients were included, 50 in the CT arm and 56 in the TI arm. A trend to a higher rate of primary end points was observed in the TI group (26.8% versus 14%, difference 12.8%, 95% CI -2.3, 27.8; P=0.105). In addition, 10 patients presented clinical events related with HIV rebound, including 8 cases of thrombocytopaenia. The CD4⁺ T-cell count significantly decreased in the TI group (even in patients with persistently high CD4⁺ T-cell counts and no clinical events) versus the CT group (median change -408 cells/μl versus -21.5 cells/μl; P<0.001), whereas a significant increase in CD8⁺ T-cell count was observed (256 cells/μl versus -59 cells/μl; P<0.001). The time to ART re-initiation was significantly associated with nadir and baseline CD4⁺ T-cell counts. Discontinuation of ART in patients with preserved immune function is followed by significant immunological impairment even in those with no clinical events, and may be associated with an increased risk of HIV-related complications. Hence, patients who stop ART voluntarily should be closely monitored, regardless of their CD4⁺ T-cell count.

Soluble CD163 Made by Monocyte/Macrophages Is a Novel Marker of HIV Activity in Early and Chronic Infection Prior to and After Anti-retroviral Therapy

CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis.

Frequent hepatitis B virus rebound among HIV–hepatitis B virus-coinfected patients following antiretroviral therapy interruption

The impact of antiretroviral therapy (ART) interruption in HIV-hepatitis B virus (HBV)-coinfected patients was examined in the Strategic Management of AntiRetroviral Therapy (SMART) study. Plasma HBV DNA was measured in all hepatitis B surface antigen-positive (HBV-positive) participants at baseline, and at months 1, 2, 4, 6, 8, 10, and 12. Among HBV-positive participants in the ART interruption (drug conservation) (n = 72) and ART continuation (virological suppression) (n = 62) arms, HBV DNA rebound of more than 1 log from baseline at months 1-4 was seen in 31-33% (P = 0.003) and 3-4% (P = 0.017), respectively. Thirteen HBV-positive participants had HBV DNA rebound of more than 3 log, including 12 in the drug conservation arm, of which eight were on tenofovir-containing regimens. Factors independently associated with a HBV DNA rebound were drug conservation arm (P = 0.0002), nondetectable HBV DNA at baseline (P = 0.007), and black race (P = 0.03). Time to ART reinitiation was shorter (7.5, 15.6, and 17.8 months; P < 0.0001) and proportion reinitiating greater (62.5, 46.5, and 39.7%; P = 0.0002) among HBV-positive participants as compared with hepatitis C virus-positive and non-HBV/hepatitis C virus participants in the drug conservation arm. No hepatic decompensation events occurred among HBV-positive participants in either arm. HBV DNA rebound following ART interruption is common and may be associated with accelerated immune deficiency in HIV-HBV-coinfected patients.

Managing Symptomatic Drug-Induced Liver Injury in HIV--Hepatitis C Virus--Coinfected Patients: A Role for Interferon

Human immunodeficiency virus (HIV)-infected patients with hepatitis C virus (HCV) coinfection are at increased risk for drug-induced liver injury (DILI) compared with patients with HIV infection alone. The mechanism underlying this observation is unknown. We hypothesized that interferon (IFN) would induce biochemical improvement through its anti-inflammatory properties and thereby facilitate the reintroduction of antiretroviral therapy (ART) in patients with DILI. Patients with symptomatic DILI were referred for evaluation; biopsy of a liver sample was performed for all patients, except 1 with clinical cirrhosis. Twelve patients with acquired immunodeficiency syndrome and symptomatic grade 3/4 hepatotoxicity received treatment with IFN and ribavirin (RBV). Seven of these patients had a history of recurrent DILI. The mean baseline CD4(+) T cell counts and HIV RNA levels were 124 cells/mm(3) and 115,369 copies/mL, respectively. Biopsies of liver samples demonstrated significant necroinflammation (mean grade, 10.3) and fibrosis (mean stage, 2.9). Three patients continued to receive ART when they began treatment with IFN-RBV; 9 reinitiated ART within an average of 12 weeks (range, 4-20 weeks) of HCV treatment initiation. All patients attained marked improvement in aminotransferases and continued to receive ART treatment during a mean follow-up regimen of 26.5 months, with subsequent virologic suppression and immunologic reconstitution (mean CD4(+) cell count increase, 251/mm(3)). However, only 1 patient maintained HCV suppression after completion of treatment with IFN-RBV. In patients with symptomatic DILI, treatment with IFN-ribavirin (RBV) led to decreases in aminotransferase levels, which enabled the reinitiation of ART. The beneficial effects of IFN-based therapy may be modulated through the suppression of proinflammatory cytokines, even in virologic nonresponders. Herein, we propose a novel mechanism for DILI, whereby HCV- and HIV-associated inflammatory mediators induce liver injury synergistically.

Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients.

To determine the effect of treatment interruptions (TI) on the evolution and persistence of drug-resistant viruses in chronically HIV-1-infected suppressed patients. The emergence of viral resistance to combination antiretroviral therapy was monitored in 11 suppressed chronically HIV-1-infected patients undergoing from one up to four sequential TI (a total of 25 TI), by genotyping of the virus for known mutations in the genes for protease and reverse transcriptase. Resistance assays were performed at the first viral rebound > 100 copies/ml. All subjects achieved resuppression of HIV-1 under the same antiretroviral therapy, regardless of the number of TI. Five of eleven patients showed no development of resistance. In the remaining six patients, the following patterns of mutations associated with viral resistance were found: one mutation (K70R), which was observed in one patient during the 1st TI and persisted during follow-up; two mutations (L90M, M184V), which were observed in four patients during the 1st TI and were intermittently present or lost following extended TI, treatment reinitiation and/or during subsequent TI; and evolution of two mutations (M184V, K219E) observed in two patients. These two mutations were not present during the 1st TI and were subsequently lost following therapy reinitiation or during the next TI. Detection of drug resistance during TI by virus genotyping assays does not predict failure to resuppress after antiretroviral therapy reinitiation nor persistence of a resistant viral population during extended interruptions or subsequent TI.