Recent Findings on the Mechanisms Involved in Tenofovir Resistance

The pyrophosphate (PPi) analogue phosphonoformic acid (PFA or foscarnet) inhibits the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1); however, the mechanisms of drug action and resistance remain elusive. Here we studied the effects of the translocational status of HIV-1 RT on drug binding and inhibition of DNA synthesis. We identified "hot spots" for inhibition during active elongation. Site-specific footprinting analyses revealed that the corresponding complexes exist predominantly in the pre-translocational state. The sensitivity to PFA is significantly reduced with sequences that show a bias toward the post-translocational state. Binding studies showed that PFA stabilizes selectively the complex in the pre-translocated configuration. These findings are consistent with a Brownian ratchet model of polymerase translocation. The enzyme can rapidly shuttle between pre- and post-translocated states. The bound inhibitor acts like a pawl of a ratchet and prevents the forward motion of HIV-1 RT, whereas the bound nucleotide binds to the post-translocated complex and prevents the reverse motion. The proposed mechanisms of RT translocation and drug action are consistent with the PFA-resistant phenotypes. We show that certain sequences and the PFA-resistant E89K mutant diminishes the stability of the pre-translocated complex. In these cases, the enzyme is seen at multiple positions around the 3' end of the primer, which provides a novel mechanism for resistance. These findings validate the pre-translocated complex as a target for the development of novel, perhaps less toxic and more potent inhibitors that block HIV-1 RT translocation.

Introduction of HIV drug-resistance testing in clinical practice.

There are 28 approved antiretroviral drugs for the treatment of HIV infection; combinations of these drugs clearly change the natural history of HIV, dramatically decreasing HIV-related morbidity and mortality and promoting and prolonging healthy survival. Despite the benefits of HIV treatment, some antiretroviral regimens may be inconvenient, toxic, and/or have suboptimal antiretroviral activity, particularly against drug-resistant viral strains. Thus, newer compounds are needed that continue to improve convenience and tolerability, reduce toxicity, and improve antiretroviral activity, particularly against drug-resistant viruses. Additionally, newer drugs may better penetrate tissue reservoirs (e.g. genital tract, central nervous system) and/or exploit new viral or cellular targets with new mechanisms of action. In addition to the direct antiretroviral action, some investigational agents may target inflammation and/or immune responses. Finally, newer formulations of antiretroviral agents may allow additional options for one-pill, once-daily dosing or allow less frequent dosing than once-daily, perhaps as infrequently as once-monthly or once-quarterly parenteral dosing. There are a number of investigational antiretroviral agents currently in development. These include newer antiretroviral agents in existing classes, including new nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and entry inhibitors. Of those in the pipeline, a few compounds are in advanced stages of development: Tenofovir alafenamide fumarate (TAF) is a nucleoside analogue reverse transcriptase inhibitor currently in phase 3 that is potent and potentially less toxic than the current TDF formulation. Doravirine (formerly MK-1439) is a non-nucleoside analogue reverse transcriptase inhibitor currently in phase 2 that demonstrates activity against NNRTI-resistant viral strains. GSK ‘744 is an integrase inhibitor currently in phase 2, being developed in a long-acting preparation. In addition there are investigational drugs with new mechanisms of action in development: BMS-663,068, is a small molecule CD4 attachment inhibitor that completed phase 1 testing. Cenicriviroc is a novel CCR5/CCR2 antagonist currently in phase 3 that offers both antiretroviral activity and the potential for an anti-inflammatory effect (through CCR2 antagonism). A number of other compounds are in earlier stages of pre-clinical and clinical development. The clinical use of these newer agents and formulations will depend on the results of clinical trials, and the timeline for development and availability. Continued progress in HIV drug development will allow improvements in the clinical care of patients living with HIV infection.

The objectives of this study were to provide individual and population-based unit cost estimates of HIV treatment and care by stage of HIV infection for adults in England and estimate the financial impact of the use of combination antiretroviral therapy. Individual unit cost estimates were calculated, based on 1997 activity data, and linked to the number of diagnosed HIV-infected individuals using statutory medical services by clinical stage of HIV infection in England during 1997 to obtain population-based cost estimates; these were compared with 1996 estimates. Most clinical guidelines now recommend the use of 3 antiretroviral agents, but cost estimates for mono and dual therapy were included as baseline estimates. Baseline costs for treating AIDS patients with zidovudine (AZT) monotherapy were estimated at £16,830 (95% CI 14,633–18,985) per patient-year which was substantially lower than the 1996 estimate; costs for asymptomatic individuals and people with symptomatic non-AIDS were £4450 (95% CI 3521–5612) and £7289 (95% CI 6169–8386) per respective patient-year which did not differ substantially from 1996. The total annual population cost estimate for HIV service provision amounted to £128 million (95% CI £109m to £147m), if all patients with HIV disease were treated with AZT monotherapy only. For all eligible patients to be treated with 2 nucleoside reverse transcriptase inhibitors (NRTI) (AZT and didanosine (ddI) or zalcitabine (ddC)), cost estimates amounted to £161m (95% CI £141m to £181m), while for triple therapy, annual estimated expenditure amounted to £185m (95% CI £165m to £206m) when a non-nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine) was included or £205m (95% CI £186m to £235m) when a protease inhibitor was included. Compared with 1996 population-based cost estimates, the estimates for monotherapy decreased by 14%, by 11% for dual therapy, by 10% for triple therapy which included a NNRTI and by 9% if a protease inhibitor was used as part of a triple therapy regimen. Similarly, compared with 1996 estimates, the proportion of total costs attributable to treating asymptomatic individuals increased by 5% and 2–3% for people with symptomatic non-AIDS, while the proportion attributable for treating people with AIDS decreased by 8–9%.

Metabolic complications of HIV therapy in children.

BackgroundHIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15–24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15–24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control.MethodsA cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes.ResultsA total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine.ConclusionsThere is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.

Introduction. Over the past 10 years, there has been an increase in HIV-1 resistance to antiretroviral drugs worldwide. HIV infection patients with low adherence to antiretroviral therapy (ART) are most often at risk of developing acquired HIV-1 resistance. The identification of key factors affecting the degree of adherence will allow timely detection of patients with a high risk of poor adherence to ART and treatment defaulting, and develop individual management tactics for such patients to reduce the risk of resistance development. Aim. To study the factors influencing adherence to ART in patients with virological failure and the effect of adherence on the risk of developing acquired HIV-1 resistance to first-line antiretroviral drugs. Materials and methods. Two hundred and seventy one patients with an confirmed diagnosis of HIV infection, with different stages of the disease, aged 21 to 59 years, who were followed-up from March 2018 to August 2022 at the Center for the Prevention and Control of AIDS (City Infectious Clinical Hospital No. 1, Novosibirsk) and received ART, were enrolled in a study. The criterion to include patients in the study was a virological breakthrough during previously effective ART with first-line drugs (when an undetectable level of HIV RNA load was recorded for 3–6 months). A retrospective analysis of the degree of adherence to ART of the studied patients with HIV infection and virological breakthrough was performed, considering various factors. The HIV-1 drug resistance testing was carried out based on the State Research Center of Virology and Biotechnology VECTOR. Results. Men predominated among the patients – 56.4% (n = 153). The average age was 35.4 ± 2.85 years. Heterosexual transmission of HIV was dominant – 64.8%. Parenteral transmission of HIV (intravenous drug abuse) accounted for 31.5% of cases. According to the results of the retrospective analysis of the degree of adherence to ART, it was found that 48.3% (131 out of 271) of patients had missed medications, including low adherence in 31.7% (86 out of 271) patients; average – in 16.6% of patients (45 out of 271). Most often, poor adherence was reported in people with parenteral HIV transmission– 75.3% compared with sexual transmission – 36% (p < 0.001), and in rural residents – 62.5% compared with urban residents – 34.1% (p < 0.001). Among men, missed medication was detected more often than in women – 57.5 and 36.4%, respectively (p < 0.001). Also, a significant factor was the lack of permanent employment – poor adherence was in 69.5% of patients in this group compared with patients having permanent employment – 26.3% (p < 0.05). On the contrary, high adherence was more often observed in female patients – 63.6% compared with male ones – 42.5%; in the presence of permanent employment – 73.7% compared with 30.5% in it’s absence; in the case of sexual transmission – 64.0% compared with parenteral transmission – 24.7%; in urban residents – 65.9% versus 37.5% in rural residents (p < 0.05). According to the totality of all mutations revealed, HIV drug-resistant variants were found in 54.6% of the patients with virological ART failure (148 out of 271). Of the 148 HIV-1 drug-resistant variants, a combination of drug resistance mutations from the group of nucleoside reverse transcriptase inhibitors (NRTIs) was most often detected and non-nucleoside reverse transcriptase inhibitors (NNRTIs) – in 60.1% (89 cases). Isolated mutations to NRTIs were found in 15.5% (23) cases, for NNRTIs – in 12.2% (18). A combination of mutations of resistance to NRTIs + integrase inhibitors (IIs) was found in 4.1% (6) patients. The proportion of patients with resistance to NRTIs and PIs (protease inhibitors) was 2% (3); to NRTIs + IIs – 1.4% (2). A combination of mutations to three classes of drugs at once was detected in 6 patients: NRTIs + NNRTIs + IIs – 2.7% (4) and NRTIs + NNRTIs + PIs – 1.4% (2). An isolated mutation to IIs was in one patient (0.6%). Conclusion. The analysis showed that non-adherence was reported in a significant part of patients – 48.3% (low – 31.7%, moderate – 16.6%). Factors contributing to poor adherence to ART were: parenteral transmission of HIV (in 75.3% of people with poor adherence); living in rural areas (in 62.5%); lack of permanent employment (in 69.5%); male sex (in 57.5%). Among patients with detected HIV drug resistance (n = 148), individuals with poor adherence prevailed (70.9%) compared with patients who did not have HIV drug resistance (23.6%) (p < 0.001). Taking into account the data obtained, when choosing the initial ART regimen, it is necessary to analyze the degree of risk of non-adherence depending on social and other factors. The high frequency of registration of HIV drug-resistant mutations found in the Novosibirsk Region necessitates timely testing for drug-resistant HIV patients with virological ART failure and the introduction of screening for primary drug resistance in patients at risk of poor adherence.

Treatment of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals with antiretroviral (ARV) drugs is highly effective in inhibiting viral replication, increasing both the duration and the quality of life (71). Regimens consisting of combinations of protease (PR), reverse transcriptase (RT), and fusion inhibitors are the current standard of care and typically reduce the circulating virus levels in previously untreated patients to below current limits of detection. Treatment failure, however, is not uncommon and is typically defined as a return to detectable levels of circulating virus, eventually resulting in decreases of CD4-cell counts and immune function and progression to AIDS. The development of viral resistance to ARV drugs is a primary cause of treatment failure (24). Extensive genetic diversity is inherent in HIV because the highly error-prone RT enzyme creates a population of variants from which drug-resistant strains can be selected during treatment (49). Many individual point mutations (single amino acid changes) or groups of point mutations in the PR, RT, or gp41 gene have been associated in clinical studies with the failure of treatment with protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), and fusion inhibitors, respectively (17, 24, 50, 52). HIV-1 strains isolated both from patients who have failed treatment and from laboratory strains modified by site-directed mutagenesis to possess specific mutations show reduced susceptibilities in vitro to one or more ARV drugs. Some point mutations are specific to individual drugs, while others confer cross-resistance to one or more drugs of the same class. Over the past several years, strains with insertions of nucleotides in the PR and the RT genes (and that thus have extra amino acids in those proteins) have been found in patients who have failed ARV drug therapy. Numerous publications have examined the origins, prevalences, in vitro susceptibilities, and replication capacities of insert-containing strains, as well as the mechanisms by which the insertions affect drug resistance. This minireview focuses on the clinically related information regarding PR and RT insert-containing strains of HIV and briefly addresses the topics of mechanism and structure.

Looking back over the development of antiretroviral therapies (ART) for the treatment of HIV infection, probably the turning point in generating a belief that there were real grounds for optimism of ‘therapeutic success’ came with the introduction of protease inhibitors (PIs) in 1995. As a component of antiretroviral therapy, PIs produced a dramatic decrease in mortality and morbidity in HIV infection [1] most clearly demonstrated by the reduction of opportunistic infections and hospital admissions. Today, a triple drug combination regimen containing nucleoside reverse transcriptase inhibitors (NRTIs) plus PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitutes the standard of care for patients commencing therapy (see Table 1). Table 1 Currently licensed antiretrovirals. Despite its success, combination ART still lacks sufficient potency and durability. Large prospective studies [2] suggest that up to 50% of HIV-positive patients will fail to achieve adequate suppression of plasma HIV RNA (i.e. < 50 copies/ml) with any of the current ART regimens. Even if this is achieved, viral rebound develops in a significant proportion of patients within 1 year of follow-up [3–5]. For example, in the Swiss cohort study [3], rebound HIV viraemia (from < 400 copies/ml to detectable) was approximately 10% per year in ART-naive patients commencing therapy and 20% in ART-experienced patients switching therapy. Although 80% of ART-naive patients achieved viral load below 400 copies/ml at 6 months, this was only sustained in 66% at 30 months and treatment changes were necessary in approximately half of patients by 24 months. In the Frankfurt cohort [4], over half of patients developed viral rebound within 12 months of achieving undetectable RNA. There are also a growing number of patients who fail treatment despite exposure to most antiretroviral agents and consequently receive salvage therapy, which may include ‘mega-ART’ regimens. Such regimens are associated with increased potential for toxicity and serious drug interactions. In this context, some of the most pressing clinical pharmacology questions are: Why do some patients fail treatment regardless of the regimen selected? How can existing therapies be improved or optimized? Will the new drugs in development show significant advantage? Treatment failure is clearly multifactorial, and may include the development of antiviral resistance, poor adherence to therapy and pharmacokinetic reasons. This review will focus on pharmacokinetic variability as an important consideration in treatment failure and current approaches to address the problem. Pharmacokinetic variability is particularly important in relation to PIs – a group of peptidomimetic drugs with considerable inter and intra-individual variability in plasma levels and marked potential for drug interactions leading to reduced or elevated PI plasma concentrations [6, 7]. Reduced concentrations will potentially compromise efficacy while elevated concentrations will predispose to adverse events. When considering the role of therapeutic drug monitoring (TDM) in antiretroviral therapy, the primary focus is therefore on PIs. However before proceeding to develop the arguments for TDM of PIs it is important to highlight the main issues around plasma concentrations of the other two main classes of antiretrovirals. For NRTIs, establishing a relationship between plasma concentration and antiviral effect has been difficult simply because it is the intracellular triphosphate anabolite that is the active moiety (Figure 1). Plasma concentrations of parent nucleosides and intracellular concentrations of triphosphates show only a weak correlation. Figure 2 displays data from studies with zidovudine (ZDV) and lamivudine (3TC) [8, 9]. Therefore meaningful data would require cell separation (i.e. to generate peripheral blood mononuclear cells, PBMCs), a technique which is time consuming, followed by analysis of the active triphosphate, a procedure that is currently available only in a handful of laboratories. This effectively precludes the routine use of TDM for NRTIs in clinical practice until such time as a more rapid throughput analytical system is developed. Figure 1 Activation pathways of nucleoside analogues. Figure 2 The relationship between intracellular nucleoside triphosphate and plasma concentration of parent drug for (a) zidovudine (ZDV) and (b) lamivudine (3TC) (○ 150 mg. • 300 mg). Note the weak correlation between area under the curve in cells ... Data from pharmacokinetic studies of NNRTIs indicate that two of the drugs, efavirenz and nevirapine, have a prolonged half-life, normally achieve adequate steady-state plasma concentrations during a dosing interval and have pharmacokinetics which are less variable than those of PIs. Although we would not entirely rule out a role for TDM of NNRTIs in some circumstances (e.g. in relation to CNS side-effects of efavirenz), presently attention is focused on PIs.

There are now exactly 20 anti-HIV drugs licenced (approved) for clinical use, and > 30 anti-HIV compounds under (pre)clinical development. The licenced anti-HIV drugs fall into five categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir disoproxil fumarate); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz); protease inhibitors (PIs: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir and fosamprenavir); and fusion inhibitors (FIs: enfuvirtide). The compounds that are currently under clinical (Phase I, II or III) or preclinical investigation are either targeted at the same specific viral proteins as the licenced compounds (i.e., reverse transcriptase [NRTIs: PSI-5004, (-)-dOTC, DPC-817, elvucitabine, alovudine, MIV-210, amdoxovir, DOT; NNRTIs: thiocarboxanilide, UC-781, capravirine, dapivirine, etravirine, rilpivirine], protease [PIs: tipranavir, TMC-114]) or other specific viral proteins (i.e., gp120: cyanovirin N; attachment inhibitors: AIs, such as BMS-488043; integrase: L-870,812, PDPV-165; capsid proteins: PA-457, α-HCG); or cellular proteins (CD4 downmodulators: CADAs; CXCR4 antagonists: AMD-070, CS-3955; CCR5 antagonists: TAK-220, SCH-D, AK-602, UK-427857). Combination therapy is likely to remain the gold standard for the treatment of AIDS so as to maximise potency, minimise toxicity and diminish the risk for resistance development. Ideally, pill burden should be reduced to once-daily dosing so as to optimise the patient’s compliance and reduce the treatment costs.

Reassessing the goal of antiretroviral therapy in the heavily pre-treated HIV-infected patient.

Virtually all the compounds that are currently used (or have been the subject of advanced clinical trials) for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents (2,2′-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)); (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity (“second” generation NNRTIs (i.e., TMC-125, DPC-083)) against those HIV strains that are resistant to the “first” generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

Emtricitabine, a nucleoside reverse transcriptase inhibitor (RTI), and tenofovir disoproxil fumarate (tenofovir DF), a nucleotide RTI, as a fixed-dose combination tablet (emtricitabine/tenofovir DF) for once-daily oral administration, are used as the nucleoside/nucleotide RTI backbone in combination with other antiretroviral agents, including ritonavir-boosted protease inhibitors (PIs), in the treatment of adults with HIV-1 infection. Emtricitabine and tenofovir DF show good activity against laboratory strains and clinical isolates of HIV-1 in vitro, although strains with resistance to emtricitabine or tenofovir have also been reported. Regimens consisting of once-daily emtricitabine/tenofovir DF 200 mg/300 mg plus lopinavir/ritonavir (in the randomized, double-blind, placebo-matched, multicentre HEAT study) or boosted atazanavir or efavirenz (in the randomized, partially-blind, multicentre ACTG 5202 trial) were effective in the initial treatment of patients with HIV-1 infection (with screening plasma HIV-1 RNA levels of >or=100,000 copies/mL in ACTG 5202). In other randomized studies, emtricitabine/tenofovir DF 200 mg/300 mg once daily was an effective backbone for boosted PI-based regimens in the initial treatment of HIV-1 infection. Treatment-experienced patients with HIV-1 infection also experienced beneficial virological effects when treated with similar regimens. Emtricitabine/tenofovir DF in combination with various boosted PIs was generally well tolerated by adults with HIV-1 infection.

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy.

Both the human immunodeficiency (HIV) and hepatitis C (HCV) viruses have been associated with insulin resistance (IR). However, our understanding of the prevalence of IR, the underlying mechanisms and predisposing factors is limited, particularly among minority populations. We conducted a study of 333 Hispanic adults including: 76 HIV monoinfected, 62 HCV monoinfected, 97 HIV/HCV co-infected and 98 uninfected controls with a specific focus on HCV infection and liver injury as possible predictors of IR. IR was measured using the Quantitative Insulin Sensitivity Check Index (QUICKI). The majority (55-69%) of participants in all groups had QUICKI values <0.350. Body mass index was associated with IR in all groups. Triglycerides were associated with IR in the uninfected control group only (-1.83, SE = 0.58, P = 0.0022). HCV was associated with IR in participants infected with HIV (-0.012, SE = 0.0046, P = 0.010). Liver injury, as measured by score to assess liver injury (FIB-4) score, was significantly associated with IR independently of HCV infection (-0.0035, SE = 0.0016, P = 0.027). In the HIV/HCV co-infected group, treatment with nucleoside reverse-transcriptase (RT) inhibitors plus non-nucleoside RT inhibitors (-0.021, SE = 0.080, P = 0.048), but not protease inhibitors (-0.000042, SE = 0.0082, P = 0.96) was associated with IR. HCV infection and antiretroviral agents, including nucleoside RT inhibitor plus non-nucleoside RT inhibitor treatment are contributors to IR in HIV infection. Liver injury, as measured by the FIB-4 score, is a predictor of IR independently of HCV infection.