Kimberly Y. Smith

Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease.

Objective: To describe the magnitude of immune restoration after long-term control of HIV-1 replication. Design: Prospective study of immune restoration in patients starting highly active antiretroviral therapy (HAART). Methods: Patients with moderately advanced HIV-1 infection (CD4 cells between 100 × 106 and 300 × 106/l) who enrolled in a trial of HAART and who had suppression of HIV-1 replication during 3 years of therapy were evaluated for phenotypic and functional indices of immune restoration. Results: Almost all immune restoration achieved occurred during the first year. The median CD4 lymphocyte count increased by 159 × 106 cells/l during the first year (P < 0.001); CD4 lymphocyte rises during the second and third years were not significant. Most decreases in activation antigen expression (CD38/HLA-DR) on CD4 and CD8 lymphocytes occurred during the first year, and after 3 years, patient lymphocytes were still abnormally activated. The proportion of CD4 lymphocytes expressing CD28 increased during the first and second years, but even after 3 years, CD28 expression on CD4 cells remained abnormally low. Lymphocyte proliferative responses to Candida normalized during the first 12 weeks of HAART while responses to tetanus increased only after immunization and enhanced responses to HIV-1 p24 antigen were not observed. Conclusions: Immune restoration was incomplete in patients who started HAART with moderately advanced HIV-1 disease and most changes occurred during the first year. These data suggest that this degree of suppression of HIV-1 replication alone will not suffice to restore immune competence. The clinical significance of incomplete reconstitution of CD4 lymphocyte number, phenotype, and proliferative function in HIV-1 infection remains to be determined.

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment.

Background:Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients. Methods:Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. Results:At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference −6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval −5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA ≥ 100 000 copies/ml or CD4+ cell counts below 50 cells/μl. Median CD4+ recovery (ABC/3TC vs. TDF/FTC, cells/μl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. Conclusion:Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Thymic Size and Lymphocyte Restoration in Patients with Human Immunodeficiency Virus Infection after 48 Weeks of Zidovudine, Lamivudine, and Ritonavir Therapy

Human immunodeficiency virus (HIV) infection is associated with progressive loss of circulating CD4+ lymphocytes. Treatment with highly active antiretroviral therapy (HAART) has led to increases in CD4+ T lymphocytes of naive (CD45RA+62L+) and memory (CD45R0+RA-) phenotypes. Thymic computerized tomography scans were obtained on 30 individuals with HIV disease to investigate the role of the thymus in cellular restoration after 48 weeks of HAART. Individuals with abundant thymic tissue had higher naive CD4+ T lymphocyte counts at weeks 2-24 after therapy than individuals with minimal thymic tissue. Individuals with abundant thymic tissue had significantly larger increases in naive CD4+ cells during the first 4 weeks of therapy. These individuals were also more likely to experience viral rebound despite comparable initial declines in plasma HIV-1 RNA. These findings suggest that there is a complex relationship among the thymus, viral replication, and lymphocyte restoration after application of HAART in HIV disease.

Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen

ObjectivesTo ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. Design and settingOpen-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States. Subjects and methodsThirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. ResultsThe LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens. ConclusionsMost HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT

BackgroundOnce-daily (QD) ritonavir 100 mg-boosted fosamprenavir 1400 mg (FPV/r100) or atazanavir 300 mg (ATV/r100), plus tenofovir/emtricitabine (TDF/FTC) 300 mg/200 mg, have not been compared as initial antiretroviral treatment. To address this data gap, we conducted an open-label, multicenter 48-week study (ALERT) in 106 antiretroviral-naïve, HIV-infected patients (median HIV-1 RNA 4.9 log10 copies/mL; CD4+ count 191 cells/mm3) randomly assigned to the FPV/r100 or ATV/r100 regimens.ResultsAt baseline, the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA (median, 4.9 log10 copies/mL [both]), CD4+ count (mean, 176 vs 205 cells/mm3). At week 48, intent-to-treat: missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 (HIV-1 RNA < 50 copies/mL: 75% (40/53) vs 83% (44/53), p = 0.34 [Cochran-Mantel-Haenszel test]); mean CD4+ count change-from-baseline: +170 vs +183 cells/mm3, p = 0.398 [Wilcoxon rank sum test]). Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar, although week 48 median fasting triglycerides were higher with FPV/r100 (150 vs 131 mg/dL). FPV/r100-treated patients experienced fewer treatment-related grade 2–4 adverse events (15% vs 57%), with differences driven by ATV-related hyperbilirubinemia. Three patients discontinued TDF/FTC because their GFR decreased to <50 mL/min.ConclusionThe all-QD regimens of FPV/r100 and ATV/r100, plus TDF/FTC, provided similar virologic, CD4+ response, and fasting total/LDL/HDL-cholesterol changes through 48 weeks. Fewer FPV/r100-treated patients experienced treatment-related grade 2–4 adverse events.

Challenges and Successes in Linking HIV-Infected Women to Care in the United States

Women currently account for 27% of new human immunodeficiency virus (HIV) infections in the United States, the majority of which are acquired through heterosexual transmission. In the United States, black and Latino persons are disproportionately affected by the HIV epidemic, a disparity that is most dramatically present among HIV-infected women. Many of these women face significant discrimination as a result of race or ethnicity and sex, and they suffer disproportionately from poverty, low health literacy, and lack of access to high-quality HIV care. As a consequence, despite the availability of highly active antiretroviral therapy (HAART), women with HIV often have delayed entry into care and experience poor outcomes. This article reviews risk factors for HIV infection in women, barriers to engagement in care, and strategies to improve linkage to HIV-related medical and social care.

Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial

BACKGROUND In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. METHODS In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809. FINDINGS Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. INTERPRETATION Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. FUNDING ViiV Healthcare and Janssen Research and Development.

Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial

BACKGROUND Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. METHODS In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir-lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. FINDINGS Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI -5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [-4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. INTERPRETATION The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. FUNDING ViiV Healthcare and Janssen R&D.

Electron beam computed tomography for assessment of coronary artery disease in HIV-infected men receiving antiretroviral therapy

Hyperlipidemia has been seen in patients receiving protease inhibitor-based antiretroviral therapy, prompting concern that such patients are at risk for accelerated coronary artery disease (CAD). To assess the risk of CAD in antiretroviral-treated HIV-infected men, we quantified coronary artery calcium (CAC), a sensitive and established marker of subclinical CAD, using electron beam computed tomography (EBCT) of coronary vessels. Sixty HIV-infected men who met the following criteria (cases) were enrolled in the study: age of 40 years or older; naive to antiretroviral therapy or use of a stable antiretroviral regimen for >or=6 months (mean duration, 25.9 months; 41 patients were receiving protease inhibitor therapy); and no known CAD or no use of lipid-lowering agents. EBCT-derived CAC scores, serum lipid levels, history of antiretroviral therapy, and risk factors for CAD were obtained. Each case was compared with three age-, sex-, and race-matched HIV-negative controls randomly selected from a database including >9000 patients who had undergone EBCT. We determined differences in the proportion of cases and controls with CAC scores of >0 (detectable calcium) and clinically significant CAC for age range. There were no statistically significant differences between the number of cases and controls with detectable CAC (33% and 39%, respectively) and clinically significant CAC (18% and 17%, respectively). This study suggests that the rate of coronary atherosclerosis among HIV-infected patients who receive short-term antiretroviral therapy with or without protease inhibitors is not higher than that among age-, sex-, and race-matched HIV-negative controls. These results need to be confirmed in larger long-term studies, with controls well matched for coronary risk factors.

HIV Risk Perception and Preexposure Prophylaxis Interest Among a Heterosexual Population Visiting a Sexually Transmitted Infection Clinic

Low perception of HIV risk despite behaviors associated with increased risk is thought to be a contributing factor for a higher prevalence of HIV in blacks than other groups in the United States. We sought to determine HIV risk perception and its impact on safer sex practices and interest in preexposure prophylaxis (PrEP). From August 1 to October 31, 2010, an anonymous survey was conducted at a sexually transmitted infection clinic asking questions about demographics, risk behaviors, and PrEP interest. Participants were categorized into high-risk, moderate-risk, and low-risk groups according to predefined HIV risk characteristics. Only heterosexual high-risk participants were further assessed for their risk perception, condom use and PrEP interest. There were 494 participants; 63% male, 70% blacks, 88% heterosexual; 83% were categorized into the high-risk group. Of the 359 heterosexual high-risk participants, 301 (84%) perceived themselves at no or low-risk. Rates of consistent condom use with vaginal, oral, and anal sex were low (<20%) in this group despite high levels of knowledge about HIV transmission risks. Rates of condom use were not affected by risk perception. No interest in PrEP was associated with low education level (adjusted odds ratio 4.97; p=0.02) and low risk perception. These findings suggest that despite having knowledge about HIV transmission risks, the majority of high-risk participants did not recognize their risks and used condoms with low frequency. Low risk perception and low education level may impact PrEP interest. Enhanced interventions are needed to improve HIV risk perception, safer sex practices, and knowledge about PrEP.