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Background. Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. Methods. Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance–failure association. Results. In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/μL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex–treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04–2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22–.98). Conclusions. In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible.

Background. Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study. Methods. The present study was a double-blind, randomized phase 2 study of vicriviroc in treatment-experienced, human immunodeficiency virus (HIV)–infected subjects experiencing virologic failure while receiving a ritonavir-containing regimen with an HIV-1 RNA level ⩾5000 copies/mL and CCR5-using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV-1 RNA levels at day 14; secondary end points included safety/tolerability and HIV-1 RNA level changes at week 24. Results. One hundred eighteen subjects were randomized with a median HIV-1 RNA level of 36,380 (4.56 log10) copies/mL and a median CD4 cell count of 146 cells/mm3. At 14 days and 24 weeks, mean changes in HIV-1 RNA level (log10 copies/mL) were greater in the vicriviroc groups (−0.87 and −1.51 [5 mg], −1.15 and −1.86 [10 mg], and −0.92 and −1.68 [15 mg]), than in the placebo group (+0.06 and −0.29) (P<.01). Grade 3/4 adverse events were similar across groups. Malignancies occurred in 6 subjects randomized to vicriviroc and in 2 to placebo. Conclusions. In HIV-1–infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

We conducted a double-blind, randomized, placebo-controlled Phase I study of a recombinant replication-defective adenovirus type 5 (rAd5) vector expressing HIV-1 Gag and Pol from subtype B and Env from subtypes A, B and C, given alone or as boost following a DNA plasmid vaccine expressing the same HIV-1 proteins plus Nef, in 114 healthy HIV-uninfected African adults. Volunteers were randomized to 4 groups receiving the rAd5 vaccine intramuscularly at dosage levels of 1×10(10) or 1×10(11) particle units (PU) either alone or as boost following 3 injections of the DNA vaccine given at 4 mg/dose intramuscularly by needle-free injection using Biojector® 2000. Safety and immunogenicity were evaluated for 12 months. Both vaccines were well-tolerated. Overall, 62% and 86% of vaccine recipients in the rAd5 alone and DNA prime - rAd5 boost groups, respectively, responded to the HIV-1 proteins by an interferon-gamma (IFN-γ) ELISPOT. The frequency of immune responses was independent of rAd5 dosage levels. The highest frequency of responses after rAd5 alone was detected at 6 weeks; after DNA prime - rAd5 boost, at 6 months (end of study). At baseline, neutralizing antibodies against Ad5 were present in 81% of volunteers; the distribution was similar across the 4 groups. Pre-existing immunity to Ad5 did not appear to have a significant impact on reactogenicity or immune response rates to HIV antigens by IFN-γ ELISPOT. Binding antibodies against Env were detected in up to 100% recipients of DNA prime - rAd5 boost. One volunteer acquired HIV infection after the study ended, two years after receipt of rAd5 alone. The HIV-1 rAd5 vaccine, either alone or as a boost following HIV-1 DNA vaccine, was well-tolerated and immunogenic in African adults. DNA priming increased the frequency and magnitude of cellular and humoral immune responses, but there was no effect of rAd5 dosage on immunogenicity endpoints. ClinicalTrials.gov NCT00124007.

Abstract Background Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions Passive-partner referral successfully identified partners with genetically-similar HIV infections—the likely source of infection—but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration NCT01450189 Persons diagnosed with acute human immunodeficiency virus (HIV)-1 infection in Malawi had low recruitment of sexual partners through passive referrals. Nearly all successfully-recruited partners had established HIV-1 infections, and 93% of these had a phylogenetically-linked virus to the acute index.

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.

► FIT GTU®-multi-HIVB was the first therapeutic HIV-1 vaccine trial conducted in South Africa. ► This plasmid DNA vaccine is safe and well-tolerated in HIV-1 infected, anteretrovial naive subjects. ► Cross subtype reactivity of subtype B derived vaccine in subtype C infected subjects was shown. ► Significant CD4 increases and VL decreases after IM vaccine were maintained for more than 2 years. ► This DNA HIV vaccine may be used as affordable prime/boost regimens alone or as an adjunct to HAART. Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU®-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4≥350cells/mm3 and pHIV-RNA≥50copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in logpHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. The GTU®-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801haplotypes.

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

The aim of this randomised controlled trial was to see if the addition of 4 mg/ml DNA-C priming given by the intramuscular route at weeks 0 and 4 to NYVAC-C at weeks 20 and 24, safely increased the proportion of participants with HIV-specific T-cell responses measured by the interferon (IFN)-γ ELISpot assay at weeks 26 and/or 28 compared to NYVAC-C alone. Although 2 individuals discontinued after the first DNA-C due to adverse events (1 vaso-vagal; 1 transient, asymptomatic elevation in alanine transaminase), the vaccines were well tolerated. Three others failed to complete the regimen (1 changed her mind; 2 lost to follow-up). Of the 35 that completed the regimen 90% (18/20) in the DNA-C group had ELISpot responses compared to 33% (5/15) that received NYVAC-C alone ( p = 0.001). Responses were to envelope in the majority (21/23). Of the 9 individuals with responses to envelope and other peptides, 8 were in the DNA-C group. These promising results suggest that DNA-C was an effective priming agent, that merits further investigation.

The genome of human immunodeficiency virus (HIV) has an average nucleotide composition strongly biased as compared to the human genome. The consequence of such nucleotide composition on HIV pathogenicity has not been investigated yet. To address this question, we analyzed the role of nucleotide bias of HIV-derived nucleic acids in stimulating type-I interferon response in vitro. We found that the biased nucleotide composition of HIV is detected in human cells as compared to humanized sequences, and triggers a strong innate immune response, suggesting the existence of cellular immune mechanisms able to discriminate RNA sequences according to their nucleotide composition or to detect specific secondary structures or linear motifs within biased RNA sequences. We then extended our analysis to the entire genome scale by testing more than 1300 HIV-1 complete genomes to look for an association between nucleotide composition of HIV-1 group M subtypes and their pathogenicity. We found that subtype D, which has an increased pathogenicity compared to the other subtypes, has the most divergent nucleotide composition relative to the human genome. These data support the hypothesis that the biased nucleotide composition of HIV-1 may be related to its pathogenicity.

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9–14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911–9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.