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.

A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor.

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell- tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1alpha-mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

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.

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.

Rapid generation of sequence variation during primary HIV-1 infection.

OBJECTIVE: HIV-1 undergoes extensive genetic variation in infected individuals. The extent of genetic variation has been examined in patients with AIDS, but little is known regarding the appearance of HIV-1 genetic variation immediately following infection during the primary phase of HIV-1 infection prior to seroconversion. DESIGN: We examined HIV-1 genetic variation during this early phase of HIV-1 infection by polymerase chain reaction (PCR) and nucleotide sequence analysis of the V4 by polymerase chain reaction (PCR) and nucleotide sequence analysis of the V4 variable region and the CD4-binding domain. RESULTS: Our results demonstrate that extensive sequence variation is seen early after infection, although a predominant HIV-1 species is maintained. CONCLUSIONS: The type of variants that occur are dynamic, changing over time, and the mutations seen are consistent with those expected from random occurrence, unlike the pattern of variation previously reported during later stages of disease.

Relative resistance of primary HIV-1 isolates to neutralization by soluble CD4.

Replication of the human immunodeficiency virus type 1 (HIV-1) underlies the pathogenesis and progression of the acquired immunodeficiency syndrome (AIDS). A soluble form of the virus receptor, CD4, has been developed as a potential therapeutic agent with good activity against laboratory strains of HIV-1 in vitro. However, quantitative virologic studies performed to date on the blood of patients receiving recombinant soluble CD4 (sCD4) demonstrated no efficacy in vivo despite good drug levels in serum. These results led us to examine the neutralizing activity of sCD4 against multiple primary HIV-1 isolates from infected patients. The findings demonstrate that primary isolates were significantly more resistant to sCD4 than were laboratory strains, which suggests a need to reevaluate CD4-based therapies and to conduct better designed preclinical studies that include experiments performed on patient viral isolates.

Virology and immunology of acute HIV type 1 infection.

Primary or acute human immunodeficiency virus type 1 (HIV-1) infection is the stage of disease when virus first disseminates throughout the body of newly infected individuals. This process results in the seeding of lymphoid tissue and the central nervous system, and the induction of a specific humoral and cellular immune response. The high level of viremia and associated immune response is often accompanied by an acute illness referred to as the acute retroviral syndrome. This syndrome often includes fever, myalgia, rash, sore throat, and lymphadenopathy. The diagnosis is confirmed by the presence of high levels of HIV in blood along with an undetectable or evolving humoral immune response. Identification of this syndrome allows for the interruption of transmission, early diagnosis and treatment, as well as the opportunity to analyze subjects at a time when the virus and immune system first interact. Studies of the virology and immunology of acute HIV infection, as well as the effect of therapy during this stage of disease has provided new insights into the pathogenesis of HIV infection. Moreover, these studies have advanced our understanding of the successes and failures of the immune response to HIV. Investigations of what constitutes an effective immune response to HIV will be vital to the success of vaccine development in the future.

Neutralization of HIV type 1 infectivity by serum antibodies from a subset of autoimmune patients with mixed connective tissue disease.

Mixed connective tissue disease (MCTD) is a rheumatic disorder with clinical similarities to HIV-1 infection, and with characteristic autoimmune anti-RNP antibodies specific for the U1 snRNP splicing complex. Anti-RNP antibodies cross-react with the HIV-1 surface, owing to multiple homologies between the gp120/41 envelope complex and the 70K protein of U1 snRNP. A key epitope of 70K, its RNA-binding site, is homologous to a dominant B and T cell epitope in the third variable loop (V3) of gp120. In this study, we tested the ability of anti-RNP sera to inhibit HIV-1 infectivity in vitro. Of nine sera tested, five were 70-99% effective in neutralizing one or more HIV-1 strains. One serum was > 99% effective in neutralizing HIV-1MN, and 86 and 77% effective against the primary isolates HIV-1(CO) and HIV-1(JR-FL), respectively, an efficacy equal to that of a pool of broadly neutralizing antibodies from HIV-1-infected subjects (HIVIG). The mean neutralizing titer of anti-RNP sera against HIV-1(JR-FL) was 3.9-fold higher than that of HIVIG. Neutralizing potency was associated with high reactivity to gp120 by ELISA, and with the presence of serum rheumatoid factor, known to enhance antibody neutralization of other viruses. The current findings provide further evidence that individuals unexposed to HIV-1 may develop immunologic resistance by alternative mechanisms, possibly including molecular mimicry, or exposure to as yet unidentified retroviruses. Thus MCTD, which involves both B and T cell reactivity to self-epitopes homologous to HIV-1, may elucidate new strategies for generating protective immunity to this virus.

Sequential determination of viral load and phenotype in human immunodeficiency virus type 1 infection.

Detailed studies of HIV viral load and phenotype were performed on sequentially cryopreserved peripheral blood mononuclear cells (PBMCs) from eight infected individuals followed in the Los Angeles Multicenter AIDS Cohort Study. Three individuals remained clinically and immunologically stable over a 5- to 8-year period, three demonstrated precipitous and two gradual declines in CD4+ T lymphocytes. Viral load in PBMCs was quantitated by limiting dilution culture and DNA PCR, while minimally passaged viral isolates were studied for their ability to induce syncytium formation in vitro and, when relevant, sensitivity to zidovudine (ZDV). Viral burden remained relatively low in those who remained clinically and immunologically stable, while increasing substantially in all five individuals who experienced a decline in CD4+ T lymphocytes. Two subjects were noted to have a switch from non-syncytium-inducing (NSI) to syncytium-inducing (SI) isolates immediately preceding a precipitous decline in CD4+ T lymphocytes, while the third individual who experienced such a decline and the two who had gradual declines did not develop SI isolates. Moreover, of the three subjects who experienced a decrease in CD4+ T lymphocyte number and were given ZDV during the study period, none were noted to develop resistance to this agent. In summary, the virology in clinically and immunologically stable individuals was characterized by relatively low viral burden in PBMCs and a predominance of NSI isolates.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Medical management of AIDS patients. Bacterial and fungal infections.

The rapid and thus far generally inexorable rise in HIV infections has led to a series of opportunistic infection that includes those caused by bacteria, yeasts, and members of the Eumycetes. The infections range in prevalence from occasional to highly prevalent, in severity from trivial to fatal, and in anatomic areas involved from local to disseminated. They occur as isolated, concurrent, or sequential infections with regard to other opportunistic diseases. Some vary in their geographic distribution. They may be newly acquired or reactivated and occur early or late in the course of HIV infection. Bacterial infections are usually easily treated, although they frequently disseminate and often recur after seemingly appropriate treatment. In contrast, all but the mildest fungal infections are difficult to treat and even more difficult or impossible to eradicate. The diagnosis of bacterial and fungal infections begins with clinical suspicion and involves relatively standard methodology. Treatment of the systemic mycoses and some bacterial infections in HIV infected patients is punctuated by exaggerated side effects of therapy, frequent relapses, and the need for maintenance suppressive therapy.

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.

Clinical experience with atovaquone: a new drug for treating Pneumocystis carinii pneumonia.

Atovaquone is a new hydroxynapthoquinone antiprotozoal agent active against Pneumocystis carinii in vitro and in animal models. The authors report an experience using atovaquone to treat 25 patients with mild to moderate P. carinii pneumonia. Eligible patients were treated for 21 days with 750 mg of atovaquone orally three times daily. Prednisone was added when the P(A-a)O2 gradient was between 35-45 mm Hg. Patients were treated under three treatment protocols. Patients in Group 1 participated in one of two randomized comparative drug trials, designed for patients with and without sulfonamide intolerance. Six of seven patients successfully completed treatment, and one patient discontinued treatment because of an adverse reaction (> 5 times baseline increase in transaminase level). Patients in Group 2 were treated with atovaquone for mild to moderate P. carinii pneumonia under a treatment Investigational New Drug protocol because of prior sulfonamide reactions. Fifteen of these 18 patients successfully completed treatment; one died from other complications during treatment and two discontinued treatment for adverse reactions (> 5 times baseline increase in transaminase levels, and a diffuse rash). Serum transaminase levels returned to normal at the end of treatment in all patients with elevated levels. All patients demonstrated clinical resolution of their pneumonia and improvement of pretreatment hypoxemia (Group 1: pretreatment PaO2 = 82 +/- 14 mm Hg, posttreatment PaO2 = 92 +/- 9 mm Hg). Overall, 21 (84%) of 25 patients successfully finished therapy without significant adverse reactions. Atovaquone appears to be an effective and well-tolerated oral treatment for mild to moderate P. carinii pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

HIV/AIDS. Assessment, testing, and natural history.

Physicians need to screen all patients for HIV risk and provide education to reduce risk. If a careful history and physical examination suggest the possibility of HIV infection, physicians should provide informed consent, counsel appropriately, and perform testing. For patients testing positive, knowledge of HIV pathogenesis helps physicians devise rational plans for treatment and patient education. The nonspecific symptoms of primary HIV infection cause it to be underrecognized and frequently not evaluated appropriately. Therapeutic intervention during primary infection may present a unique opportunity to attenuate disease caused by HIV.

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.

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.

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.