Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

Predictors of CNS injury as measured by proton magnetic resonance spectroscopy in the setting of chronic HIV infection and CART.

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

Herpes simplex virus type 2 seroprevalence and incidence in acute and chronic HIV-1 infection.

Herpes simplex virus type 2 (HSV-2) HIV co-infection is common and associated with increased risk of HIV transmission. HSV-2 seroprevalence was assessed on stored samples from baseline and one year follow-up from 81 patients identified with acute HIV infection and 81 age-matched chronically infected men. HSV-2 seroprevalence at baseline was lower for those with acute rather than chronic HIV-infection, 51.9 versus 71.6% (P = 0.01); relative risk 0.72 (95% confidence interval [CI] 0.57-0.92). Since HSV-2 seroprevalence is lower in those newly HIV-infected, the diagnosis of early HIV infection may allow for counselling to reduce subsequent HSV-2 acquisition.

Seminal plasma HIV levels in men with asymptomatic sexually transmitted infections.

The effect of asymptomatic sexually transmitted urethral infections on human immunodeficiency virus (HIV) RNA viral load in semen is poorly defined. We studied five such patients. Those on antiretrovirals (n = 2) had lower seminal plasma viral loads (SPVL) (2.11 and 1.98 log(10) copies/mL) than those not on antiretrovirals (n = 3) (2.27-3.78 log(10) copies/mL). One patient who was not taking antiretrovirals had a 94% decline in SPVL after treatment of asymptomatic Chlamydia trachomatis urethritis, suggesting that asymptomatic infection may be a co-factor for HIV transmission.

Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals.

Studies on human immunodeficiency virus type 1 (HIV-1) diversity are critical for understanding viral pathogenesis and the emergence of immune escape variants and for design of vaccine strategies. To investigate HIV-1 population genetics, we used single-genome sequencing to obtain pro-pol and env sequences from longitudinal samples (n = 93) from 14 acutely or recently infected patients. The first available sample after infection for 12/14 patients revealed HIV-1 populations with low genetic diversity, consistent with transmission or outgrowth of a single variant. In contrast, two patients showed high diversity and coexistence of distinct virus populations in samples collected days after a nonreactive enzyme-linked immunosorbent assay or indeterminate Western blot, consistent with transmission or outgrowth of multiple variants. Comparison of PR and RT sequences from the first sample for all patients with the consensus subgroup B sequence revealed that nearly all nonsynonymous differences were confined to identified cytotoxic T-lymphocyte (CTL) epitopes. For HLA-typed patients, mutations compared to the consensus in transmitted variants were found in epitopes that would not be recognized by the patient's major histocompatibility complex type. Reversion of transmitted mutations was rarely seen over the study interval (up to 5 years). These data indicate that acute subtype B HIV-1 infection usually results from transmission or outgrowth of single viral variants carrying mutations in CTL epitopes that were selected prior to transmission either in the donor or in a previous donor and that reversion of these mutations can be very slow. These results have important implications for vaccine strategies because they imply that some HLA alleles could be compromised in newly acquired HIV infections.

The prevalence of transmitted antiretroviral drug resistance in treatment-naïve patients and factors influencing first-line treatment regimen selection.

OBJECTIVES: To estimate the prevalence of transmitted antiretroviral (ARV) drug resistance, and to assess whether resistance testing influences first-line ARV regimen selection. METHODS: Data on patients' characteristics were collected through questionnaires. ARV drug resistance was tested by genotypic methods and defined by Quest-Stanford classification rule. Physicians reported the intended and actual treatments and the factors considered in treatment selection. RESULTS: Two hundred and twenty-eight patients were included. The prevalence of ARV drug resistance was 12.1%, with 9.8% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4.5% for nucleoside reverse transcriptase inhibitors and 1.8% for protease inhibitors (PIs). Pill burdens, dosing frequency and physicians' experience with regimens were the major factors considered in treatment selection. The intended and actual treatment differed for 73 and 44% of the patients with and without ARV drug resistance, respectively [odds ratio (95% confidence interval, CI)=3.6 (1.5-9.0), P=0.006]. NNRTI-based regimens were intended for 10 patients with resistance to NNRTIs; these patients were prescribed PI-based regimens after genotypic testing. CONCLUSIONS: Transmitted ARV drug resistance was detected in 12.1% of treatment-naïve patients, with resistance to NNRTIs the most common. Resistance-testing results played a partial role in first-line treatment selection. However, resistance to NNRTIs pre-empted NNRTI use.

Hepatitis C virus infection and neurocognitive function.

Hepatitis C virus (HCV) infection may be associated with neurocognitive deficits. The Hemophilia Growth and Development Study enrolled HIV-infected and HIV-uninfected patients and a group of nonhemophiliac siblings. After controlling for multiple factors, HCV monoinfection was not associated with deficits in adaptive behavior, intelligence, or attention/concentration.

The epidemiology of invasive pulmonary aspergillosis at a large teaching hospital.

OBJECTIVE: To characterize the epidemiology of invasive pulmonary aspergillosis (IPA). DESIGN: A retrospective case series. SETTING: An 850-bed, academic, tertiary-care medical center. PARTICIPANTS: Adult inpatients, between January 1, 1990, and December 31, 1998, with either a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. METHODS: We reviewed medical records and categorized case-patients as definitive or probable and acquisition of IPA as nosocomial, indeterminate, or community using standard definitions. To determine the rate of aspergillus respiratory colonization, we identified all inpatients who had a respiratory culture positive for Aspergillus species without a histopathology report consistent with IPA or a discharge diagnosis of aspergillosis. Three study intervals were defined: interval 1, 1990 to 1992; interval 2, 1993 to 1995; and interval 3, 1996 to 1998. Carpeting in rooms for patients following heart-lung and liver transplant was removed and ceiling tiles were replaced during interval 1; a major earthquake occurred during interval 2. RESULTS: 72 case-patients and 433 patients with respiratory colonization were identified. Acquisition was nosocomial for 18 (25.0%), indeterminate for 9 (12.5%), and community-acquired for 45 (62.5%) case-patients. Seventeen (23.6%) of the 72 case-patients had prior transplants, including 15 solid organ and 2 bone marrow. The IPA rate per 100 solid organ transplants (SOTs) decreased from 2.45 during interval 1 to 0.93 during interval 2 and to 0.52 during interval 3 (chi-square for trend, 5.44; P<.05). The hospitalwide IPA rate remained stable at 0.03 per 1,000 patient days. CONCLUSIONS: The SOT IPA rate decreased after intervals 1 and 2, although the hospitalwide IPA rate remained stable during the study period. Post-earthquake hospital demolition and construction occurring after interval 2 was not associated with an increase in the rate of IPA at our institution.

Antibody from patients with acute human immunodeficiency virus (HIV) infection inhibits primary strains of HIV type 1 in the presence of natural-killer effector cells.

The partial control of viremia during acute human immunodeficiency virus type 1 (HIV-1) infection is accompanied by an HIV-1-specific cytotoxic T-lymphocyte (CTL) response and an absent or infrequent neutralizing antibody response. The control of HIV-1 viremia has thus been attributed primarily, if not exclusively, to CTL activity. In this study, the role of antibody in controlling viremia was investigated by measuring the ability of plasma or immunoglobulin G from acutely infected patients to inhibit primary strains of HIV-1 in the presence of natural-killer (NK) effector cells. Antibody that inhibits virus when combined with effector cells was present in the majority of patients within days or weeks after onset of symptoms of acute infection. Furthermore, the magnitude of this effector cell-mediated antiviral antibody response was inversely associated with plasma viremia level, and both autologous and heterologous HIV-1 strains were inhibited. Finally, antibody from acutely infected patients likely reduced HIV-1 yield in vitro both by mediating effector cell lysis of target cells expressing HIV-1 glycoproteins and by augmenting the release of beta-chemokines from NK cells. HIV-1-specific antibody may be an important contributor to the early control of HIV viremia.

Relation between HIV-1 and hepatitis C viral load in patients with hemophilia.

Coinfection with hepatitis C virus (HCV) and HIV-1 is common in patients with hemophilia and in intravenous drug users. Little, however, is known about the relation between HIV-1 and HCV coinfection and the effects on HCV clearance and pathogenesis. We examined data from 207 HIV-1-infected and 126 HIV-1-uninfected patients with hemophilia enrolled in the multicenter Hemophilia Growth and Development Study. Participants were observed during prospective follow-up for approximately 7 years with annual measurements of alanine aminotransferase (ALT), CD4+ cells, and HCV and HIV-1 RNA levels. Clearance of HCV was more likely to occur in those uninfected with HIV-1 (14.3 versus 2.5%; odds ratio [OR] 4.79; 95% confidence interval [CI], 1.63-14.08, p =.005) and was more common with decreasing age (OR, 1.23; 95% CI, 1.04-1.47; p =.017). HCV RNA levels were higher throughout the 7 years of follow-up in those HIV-1-infected (p <.001). In the HIV-1-infected participants, baseline CD4+ cells were inversely related to HCV RNA with every 100-cell increase associated with a 0.19 log10 copy/ml decrease in HCV RNA (p =.002), and HIV-1 and HCV RNA levels were directly related (p =.008). Increasing HCV RNA levels were also associated with significantly higher ALT levels regardless of HIV-1 infection status. These results demonstrate that HIV-1/HCV co-infection is associated with a reduced likelihood of HCV clearance and that higher levels of HCV RNA are associated with increased hepatic inflammation.

The effect of plasma human immunodeficiency virus RNA and CD4(+) T lymphocytes on growth measurements of hemophilic boys and adolescents.

OBJECTIVE: The investigation examined the associations of plasma human immunodeficiency virus (HIV) RNA and CD4(+) T lymphocytes with height, weight, skeletal maturation, testosterone levels, and height velocity for hemophilic children and adolescents with HIV infection in the Hemophilia Growth and Development Study. STUDY DESIGN: Two hundred seven participants were evaluated over 7 years. RESULTS: A threefold increment in baseline plasma HIV RNA was associated with a 0.98-cm decrease in height and a 1.67-kg decrease in weight; 100-cells/microL decrements in baseline CD4(+) were associated with a 2.51-cm decrease in height and a 3.83-kg decrease in weight. Participants with high plasma HIV RNA (>3125 copies/mL) experienced significant delay in achieving maximum height velocity and lower maximum velocity compared with those with low viral load. The high CD4(+) (>243)/low plasma HIV RNA group had earlier age at maximum height velocity compared with the other 3 groups and higher maximum height velocity compared with the low CD4(+)/high plasma HIV RNA and low CD4(+)/low plasma HIV RNA groups. Decrements in CD4(+) were associated with decreases in bone age and testosterone level. CONCLUSIONS: CD4(+) and HIV RNA were important in predicting growth outcomes.

Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network.

BACKGROUND: The optimal approach for diagnosing primary HIV-1 infection has not been defined. OBJECTIVE: To determine the usefulness of symptoms and virologic tests for diagnosing primary HIV-1 infection. DESIGN: Prospective cohort study. SETTING: A teaching hospital in Los Angeles and a university research center in San Diego, California. PATIENTS: 436 patients who had symptoms consistent with primary HIV infection. MEASUREMENTS: Clinical information and levels of HIV antibody, HIV RNA, and p24 antigen. RESULTS: Primary infection was diagnosed in 54 patients (12.4%). The sensitivity and specificity of the p24 antigen assay were 88.7% (95% CI, 77.0% to 95.7%) and 100% (CI, 99.3% to 100%), respectively. For the HIV RNA assay, sensitivity was 100% and specificity was 97.4% (CI, 94.9% to 98.9%). Fever, myalgia, rash, night sweats, and arthralgia occurred more frequently in patients with primary infection (P < 0.05). CONCLUSIONS: No sign or symptom allows targeted screening for primary infection. Although assays for HIV RNA are more sensitive than those for p24 antigen in diagnosing primary infection, they are more expensive and are more likely to yield false-positive results.

Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs.

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.

HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells.

Inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1) may inhibit cytoplasmic retinoic acid-binding proteins, cytochrome P450 isoforms, as well as P-glycoproteins. These features of the protease inhibitors might enhance the activity of retinoids. To explore this hypothesis, myeloid leukemia cells were cultured with all-trans retinoic acid (ATRA) either alone or in combination with the HIV-1 protease inhibitors indinavir, ritonavir, and saquinavir. Consistent with the hypothesis, the HIV-1 protease inhibitors enhanced the ability of ATRA to inhibit growth and induce differentiation of HL-60 and NB4 myeloid leukemia cells, as measured by expression of CD11b and CD66b cell surface antigens, as well as reduction of nitroblue tetrazolium. Growth of ATRA-resistant UF-1 cells was also inhibited when cultured with the combination of ATRA and indinavir. Moreover, indinavir enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPepsilon messenger RNA in NB4 cells by 9.5-fold. Taken together, the results show that HIV-1 protease inhibitors enhance the antiproliferative and differentiating effects of ATRA on myeloid leukemia cells. An HIV-1 protease inhibitor might be a useful adjuvant with ATRA for patients with acute promyelocytic leukemia and possibly retinoid-resistant cancers.

Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites.

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infection have been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

Primary HIV infection. Current trends in transmission, testing, and treatment.

In the changing kaleidoscope of HIV disease, early detection of primary infection has become increasingly important. Primary care physicians who recognize the signs and symptoms are in an ideal position to diagnose the disease at an early stage and to help stem the tide of new infections in the community. In this article, Drs Yu and Daar discuss current strategies for early diagnosis, including recommended testing and steps to prevent transmission of the virus, and present the latest thinking about antiretroviral therapy during primary HIV infection.

Modeling plasma virus concentration during primary HIV infection.

During primary HIV infection the viral load in plasma increases, reaches a peak, and then declines. Phillips has suggested that the decline is due to a limitation in the number of cells susceptible to HIV infection, while other authors have suggested that the decline in viremia is due to an immune response. Here we address this issue by developing models of primary HIV-1 infection, and by comparing predictions from these models with data from ten anti-retroviral, drug-naive, infected patients. Applying nonlinear least-squares estimation, we find that relatively small variations in parameters are capable of mimicking the highly diverse patterns found in patient viral load data. This approach yields an estimate of 2.5 days for the average lifespan of productively infected cells during primary infection, a value that is consistent with results obtained by drug perturbation experiments. We find that the data from all ten patients are consistent with a target-cell-limited model from the time of initial infection until shortly after the peak in viremia. However, the kinetics of the subsequent fall and recovery in virus concentration in some patients are not consistent with the predictions of the target-cell-limited model. We illustrate that two possible immune response mechanisms, cytotoxic T lymphocyte destruction of infected target cells and cytokine suppression of viral replication, could account for declines in viral load data not predicted by the original target-cell-limited model. We conclude that some additional process, perhaps mediated by CD8+ T cells, is important in at least some patients.

Dual protease inhibitor therapy in the management of the HIV-1.

Throughout the first 20 years of the HIV-1 epidemic, there have been tremendous advances in the development of antiretroviral therapy (ART). In 1995, the availability of protease inhibitors (PI) as part of triple drug regimens resulted in durable viral suppression with an associated decline in HIV-1-related morbidity and mortality. Despite this early success, limitations of therapy have become apparent. In particular, the need for highly potent antiviral regimens, the importance of outstanding adherence to therapy, drug-related toxicity and the increasing problem of drug-drug and drug-food interactions. Dual PI therapy has been investigated with the hope of overcoming these problems. Select PI combinations may result in synergistic antiviral activity with enhanced viral suppression. Moreover, the ability of select agents to inhibit the cytochrome P450 (CYP450) system results in pharmacologic enhancement that allows for dosing with fewer pills on a less frequent basis, both of which can enhance drug adherence. Furthermore, these pharmacologic interactions can overcome drug-drug and drug-food interactions. Finally, the ability to increase drug levels using certain PI combinations may allow for drug concentrations to exceed those needed to inhibit resistant strains of HIV-1. The rationale for using dual PI therapy, along with the results of clinical trials using various PI combinations in treatment-naïve and experienced patients, is reviewed in this article.