When it rains, it pours: Early treatment with tecovirimat of cardiac complications associated with monkeypox infection in a person with HIV and previously undiagnosed Lyme disease. A case report.

Cardiac involvement, such as myocarditis and pericarditis, can be a severe complication of monkeypox virus (mpox) infection and could be related to other co-infections with cardiac involvement. Tecovirimat is an antiviral specifically designed to inhibit smallpox infection diffusion and approved by the FDA for other Orthopoxvirus infections; its efficacy in mpox-infected patients is not well established. We present the case of a cardiac complication during mpox infection in a previously undiagnosed Lyme disease in a 42-year-old man living with HIV. Two days after the typical maculopapular rash, the patient reported a rise in body temperature up to 39 °C, chest pain without irradiation, and shortness of breath. We found an increase in troponin level, a slight reduction in ejection fraction, and grade 2 AV block (Mobitz 1 and 2) with frequent sinus pauses (the longest of 10.1 s). Given the suspicion of myopericarditis with cardiac conduction system involvement, the patient was admitted to the Intermediate Care Unit for continuous monitoring and further evaluation. Treatment included Ibuprofen 600 mg every 12 hours (bid) and colchicine 1 mg once daily for anti-inflammatory purposes. Concomitantly, treatment with tecovirimat was started at 600 mg bid for a total of 14 days. Cardiac MRI with gadolinium showed mild interstitial edema and pericardial enhancement. However, despite the clinical and laboratory resolution of the acute phase, bradycardia with episodes of AV block persisted at follow-up, suggesting the possibility of an additional etiology. Thus, the patient was investigated for Lyme disease because high-degree AV block is the most common presentation of Lyme carditis. Serological results evidenced a previous Borrelia burgdorferi senso latu. We decided to start treatment with doxycycline 100 mg every 12h, even pending the uncertainty of the role of a previous Lyme disease in determining the cardiac rhythm disturbances. At the evaluation on day 44, the patient was systemically well, and after cardiologist consultation, pace-maker implantation was not deemed indicated. This case underscores the importance of considering alternative causes of carditis when the clinical picture remains unclear or persists after the acute phase.

Case Report: Intravenous Pentamidine Rescue Treatment for Active Chronic Visceral Leishmaniasis in an HIV-1 Infected Patient.

The management of visceral leishmaniasis (VL) in HIV-infected patients is complex because of high mortality rates, toxic drug-related side effects, and a high risk of treatment failure and relapse. We report a case of active chronic VL in an HIV-1-infected woman presenting multiple secondary VL episodes over 7 years leading to massive splenomegaly and blood transfusion-dependent anemia despite several treatment courses and secondary prophylaxis. The patient was finally successfully treated with rescue treatment based on intravenous pentamidine. Twenty months after discontinuation of pentamidine the patient presented complete clinical and parasitological response. In patients with active chronic VL, treatment with intravenous pentamidine can be effective and should be considered as rescue treatment.

Prevalence and factors associated with HIV-1 multi-drug resistance over the past two decades in the Italian ARCA database.

Despite successful antiretroviral therapy (ART), patients infected with human immunodeficiency virus (HIV) can develop multi-class drug resistance (MDR). This retrospective study aimed to explore the prevalence of HIV-1 drug resistance over the past two decades by focusing on HIV-MDR and its predictors. ART-experienced patients with HIV with results from at least one plasma genotypic resistance test (GRT) from 1998 to 2018, from the Antiviral Response Cohort Analysis database, were included in this study. The temporal trend of resistance to any drug class was evaluated by considering all GRTs. Prevalence and predictors of HIV-MDR were analysed by consideration of cumulative GRTs. Among 15 628 isolates from 6802 patients, resistance to at least one drug class decreased sharply from 1998 to 2010 (1998-2001: 78%; 2008-2010: 59%; P<0.001) and then remained relatively constant at approximately 50% from 2011 to 2018, with the proportion of isolates with HIV-MDR also stable (approximately 9%). By evaluating factors associated with cumulative HIV-MDR, the following factors were found to be associated with increased risk of HIV-MDR on multi-variate analysis: male gender; sexual and vertical transmission; number of previous protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-NRTIs; previous exposure to integrase strand transfer inhibitors, enfuvirtide and maraviroc; and co-infection with hepatitis B virus. In contrast, a nadir CD4 cell count ≥200 cells/mm3, starting first-line ART in 2008 or later and co-infection with hepatitis C virus were associated with lower risk of HIV-MDR. In conclusion, this study revealed that HIV-1 drug resistance has been stable since 2011 despite its dramatic decrease over the past two decades. HIV-MDR is still present, although at a lower rate, suggesting the need for continuous surveillance and accurate management of ART-experienced patients with HIV.

Focal spleen lesions in visceral leishmaniasis, a neglected manifestation of a neglected disease: report of three cases and systematic review of literature.

BACKGROUND: The Mediterranean area is endemic for the zoonotic form of visceral leishmaniasis (VL) caused by Leishmania infantum, a species which has been recently associated with unexpected epidemiological and clinical features. METHOD: We report the result of a systematic review of the literature on VL unusually presenting with spleen focal lesions, including three previously unpublished cases. RESULTS: A total of 28 cases of VL with multiple spleen focal lesions were retrieved. Twenty-six (93%) were acquired in the Mediterranean area, where L. infantum is endemic. Thirteen cases were diagnosed in children, and the remaining 15 cases in middle-aged adults, of whom 9 were immunosuppressed. Four patients (14%) underwent diagnostic splenectomy, while the diagnosis was confirmed by less invasive techniques in the remaining patients. The most common radiological patterns were: multiple subcentimetric or centimetric spleen lesions (size ≤ 1 cm in 14 of 19 cases, 74%), hypoechoic at ultrasonography (25 of 26 cases, 99%) and hypodense at CT scan (9 of 10 cases, 90%). PET-CT (available for four patients) showed an intense FDG spleen uptake. MRI and contrast-enhanced ultrasonography, available for two and one cases each, showed complex patterns. CONCLUSIONS: VL must be added to the list of possible differential diagnosis of spleen focal lesions and health care provider awareness about this condition will avoid unnecessary invasive diagnostic procedures.

Cardiovascular risk in advanced naïve HIV-infected patients starting antiretroviral therapy: Comparison of three different regimens - PREVALEAT II cohort.

BACKGROUND AND AIMS: PREVALEAT (PREmature VAscular LEsions and Antiretroviral Therapy) II is a multicenter, longitudinal cohort study aimed at the evaluation of cardiovascular risk among advanced HIV-positive, treatment-naïve patients starting their first therapy. We hypothesized that these patients, present a higher cardiovascular (CV) risk. METHODS: The study included all consecutive naïve patients with less than 200 CD4 cells/ml starting antiretroviral therapy. Our primary objective was to evaluate changes in carotid intima- media thickness (IMT). Secondary endpoints included changes in flow mediated vasodilation (FMD), inflammatory markers, triglycerides and cholesterol. Patients were evaluated at time 0, and after 3, 6 and 12 months. RESULTS: We enrolled 119 patients, stratified into three different groups: patients receiving atazanavir/ritonavir boosted (ATV/r) based regimens, efavirenz (EFV) based regimens and darunavir/ritonavir boosted (DRV/r) based regimens. At baseline, advanced naïve patients showed a relevant deterioration of CV conditions in terms of traditional CV risk factors, endothelial dysfunction and serum biomarkers. During the 12-month follow up period, mean blood lipids significantly increased: total cholesterol from 159 to 190 mg/dL, HDL-C from 31 to 41 mg/dL, and LDL-C from 99 to 117 mg/dL. D-dimers steadily decreased (median level 624 at baseline and 214 at T3), whereas ICAM and VCAM consistently raised. DRV/r and ATV/r determined a more marked decrease of D-dimers as compared to EFV. Regarding the epi-aortic changes (IMT >1 mm or presence of atherosclerotic plaques), patients in the DRV/r group were at risk of developing pathological IMT during the study (OR 6.0, 95% CI 0.9-36.9), as compared to EFV ones. CONCLUSIONS: CV risk was elevated in advanced naïve patients and tended to remain high in the first year of therapy.

Epi-aortic lesions, pathologic FMD, endothelial activation and inflammatory markers in advanced naïve HIV-infected patients starting ART therapy.

INTRODUCTION: PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV-infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART). PATIENTS AND METHODS: All consecutive naïve patients with CD4 cell count<200/mL starting any PI/r-based or NNRTI-based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi-aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM-1 and VCAM-1) and inflammatory markers (IL-6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co-infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ(2) nonparametric method. RESULTS: In Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200. CONCLUSIONS: Our data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow-up epi-aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM-1 significantly worsens during the period of observation; also VCAM-1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D-dimers and high sensitivity C-reactive protein (hsCRP). IL-6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve-month follow-up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non-specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima-media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.

Novel antiretroviral drugs and renal function monitoring of HIV patients.

Chronic kidney disease is a major comorbidity in patients affected by HIV infection. In addition, the introduction of new antiretroviral agents that interact with creatinine transporters is raising some concerns. In this review we analyze the currently available data about three new antiretroviral drugs and one new pharmacokinetic enhancer. Three of them (rilpivirine, cobicistat, dolutegravir) have shown some interactions with renal function, while tenofovir alafenamide fumarate reduces the plasmatic concentration of the parent drug. The future use of tenofovir alafenamide seems to be encouraging in order to reduce the renal interaction of tenofovir. Rilpivirine, cobicistat, and dolutegravir reduce the tubular secretion of creatinine, inducing a decrease of estimated glomerular filtration rate according to creatinine. Rilpivirine and dolutegravir block the uptake of creatinine from the blood, inhibiting organic cation transporter 2, and cobicistat interacts with the efflux inhibiting multidrug and toxin extrusion protein 1. This effect can then be considered a "reset" of the estimated glomerular filtration rate according to creatinine. However, clinicians should carefully monitor renal function in order to identify possible alterations suggestive of a true renal functional impairment. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimation of glomerular filtration rate would be desirable. However, at the moment, other methods of direct glomerular filtration rate measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate glomerular filtration rate is still recommended. Also, tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid.

The problem of renal function monitoring in patients treated with the novel antiretroviral drugs.

Chronic kidney disease (CKD) is currently considered a major comorbidity in patients affected by HIV infection. In addition, new generation antiretroviral drugs that interact with creatinine transporters were recently introduced. Rilpivirine, dolutegravir, and cobicistat, with different mechanisms, inhibit the amount of tubular secretion of creatinine causing a slight increase in serum creatinine levels and consensual eGFRcreat reduction. This will require an unprecedented attention to renal issues, because the new drugs can also be associated to old antiretroviral drugs that may exert renal toxic effects. Owing to the interference of these drugs with creatinine secretion, an alternative way of estimating GFR would be desirable. At the moment, methods of direct GFR measurement have a high impact on the patient, are not readily available, or are not reliable in HIV patients. Consequently, use of classic formulas to estimate GFR is still recommended, considering the apparent reduction of eGFRcreat due to these drugs. Tubular function needs to be carefully monitored with simple tests such as proteinuria, phosphatemia, urinary excretion of phosphate, normoglycemic glycosuria, and excretion of uric acid. More specific and sensitive markers of tubular damage are still not readily available in all clinical labs. HIV patients treated by the novel drugs need to be monitored on a monthly basis for the first 3 months. Subsequent monitoring should be performed on a quarterly basis or guided by comorbidities.

Phylogenetic analysis provides evidence of interactions between Italian heterosexual and South American homosexual males as the main source of national HIV-1 subtype C epidemics.

The HIV-1 clade C is prevalent worldwide and spread from Africa to South East Asia and South America early in the course of the epidemic. As a consequence of migration waves about 13% of the Italian HIV-1 epidemic is sustained by this clade. Two hundred fifty-four C pol sequences from the Italian ARCA database collected during 1997-2011 were analyzed. Epidemiological networks and geographical fluxes were identified through phylogeny using Bayesian approaches. Patients' country of origin was Italy, Africa, South America, and South East Asia for 44.9%, 23.6%, 4.7%, and 1.6%, respectively. Heterosexuals and men having sex with men accounted for 83.2% and 16.8%, respectively. Modality of infection was distributed differently: heterosexuals were largely prevalent among Italians (84.1%) and Africans (95.3%), while men having sex with men predominated among South Americans (66.7%). Eight significant clusters encompassing 111 patients (43.7%) were identified. Comparison between clustering and non-clustering patients indicated significant differences in country of origin, modality of infection and gender. Men having sex with men were associated to a higher probability to be included in networks (70% for men having sex with men vs. 30.3% for heterosexuals). Phylogeography highlighted two significant groups. One contained Indian strains and the second encompassed South Americans and almost all Italian strains. Phylogeography indicated that the spread of C subtype among Italians is related to South American variant. Although Italian patients mainly reported themselves as heterosexuals, homo-bisexual contacts were likely their source of infection. Phylogenetic monitoring is warranted to guide public health interventions aimed at controlling HIV infection.

Virological and immunological response to antiretroviral regimens containing maraviroc in HIV type 1-infected patients in clinical practice: role of different tropism testing results and of concomitant treatments.

We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatment-experienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA <50 copies/ml and immunological response as time to a CD4 cell count increase of ≥ 100/µl from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log10 higher: HR 1.29, 95% CI 1.05-1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96-4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.

Safety and durability in a cohort of HIV-1 positive patients treated with once and twice daily darunavir-based therapy (SCOLTA Project).

OBJECTIVE: To evaluate safety and durability of once-daily and twice-daily darunavir/ritonavir (DRV/r)-based treatment in HIV patients in clinical practice. METHODS: The Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) project is a prospective, observational, multicenter cohort created to assess the incidence of adverse events in patients receiving new antiretroviral drugs. Twenty-five Italian infectious diseases centers enroll patients and collect their data through this on-line system. Periodical evaluations of these patients, including physical examination and laboratory tests, were performed at baseline and every 6 months. RESULTS: Four hundred and twenty-nine patients were enrolled since May 2006. Eighty-five patients (19.8%) were prescribed once-daily DRV/r; 31 of them were treatment-naïve (36.5%). Among 54 (63.5%) treatment-experienced patients, 21 (38.9%) had undetectable viral load and started once-daily DRV/r as a simplification regimen. Patients on twice-daily regimen were older, more frequently lipodystrophic, HCV-coinfected, and in CDC stage C. In the following 24 months of follow-up, the viral load steadily decreased as well as the CD4 cell count rose. The reason for discontinuation did not significantly differ between groups. Mean blood glucose (BG) change from baseline did not show significant difference between groups, as well as high density lipoprotein cholesterol (HDL-C), triglycerides (TGL) and alanine transaminase (ALT). The survival curve shows that patients in the once-daily regimen withdrew treatment more frequently than those on twice-daily regimen (Log Rank Chi(2)P=0.009). CONCLUSION: Our study showed that DRV/r administrated both once daily or twice daily was safe and well tolerated with few discontinuations due to adverse events.

HIV-1 subtype F1 epidemiological networks among Italian heterosexual males are associated with introduction events from South America.

About 40% of the Italian HIV-1 epidemic due to non-B variants is sustained by F1 clade, which circulates at high prevalence in South America and Eastern Europe. Aim of this study was to define clade F1 origin, population dynamics and epidemiological networks through phylogenetic approaches. We analyzed pol sequences of 343 patients carrying F1 subtype stored in the ARCA database from 1998 to 2009. Citizenship of patients was as follows: 72.6% Italians, 9.3% South Americans and 7.3% Rumanians. Heterosexuals, Homo-bisexuals, Intravenous Drug Users accounted for 58.1%, 24.0% and 8.8% of patients, respectively. Phylogenetic analysis indicated that 70% of sequences clustered in 27 transmission networks. Two distinct groups were identified; the first clade, encompassing 56 sequences, included all Rumanian patients. The second group involved the remaining clusters and included 10 South American Homo-bisexuals in 9 distinct clusters. Heterosexual modality of infection was significantly associated with the probability to be detected in transmission networks. Heterosexuals were prevalent either among Italians (67.2%) or Rumanians (50%); by contrast, Homo-bisexuals accounted for 71.4% of South Americans. Among patients with resistant strains the proportion of clustering sequences was 57.1%, involving 14 clusters (51.8%). Resistance in clusters tended to be higher in South Americans (28.6%) compared to Italian (17.7%) and Rumanian patients (14.3%). A striking proportion of epidemiological networks could be identified in heterosexuals carrying F1 subtype residing in Italy. Italian Heterosexual males predominated within epidemiological clusters while foreign patients were mainly Heterosexual Rumanians, both males and females, and South American Homo-bisexuals. Tree topology suggested that F1 variant from South America gave rise to the Italian F1 epidemic through multiple introduction events. The contact tracing also revealed an unexpected burden of resistance in epidemiological clusters underlying the need of public interventions to limit the spread of non-B subtypes and transmitted drug resistance.

High burden of transmitted HIV-1 drug resistance in Italian patients carrying F1 subtype.

BACKGROUND: Transmitted drug resistance (TDR) is mainly restricted to individuals carrying B subtype, with low prevalence among non-B subtypes when grouped together. Subtype F1 is the most frequent non-B variant found in subjects living in Italy, allowing a specific assessment of TDR associated with this clade. METHODS: We analysed pol sequences of HIV-1-positive individuals carrying the F1 variant included in the Antiretroviral Resistance Cohort Analysis database in the 1998-2009 period. Mutations were analysed with the Surveillance Drug Resistance Mutation and the International AIDS Society lists for naive and treated patients, respectively. RESULTS: Among 343 HIV-1-infected patients carrying an F1 subtype, resistance was evaluated in a subset of 221 patients whose treatment status was known (169 drug naive and 52 drug experienced). The prevalence of TDR was 15.4% (11.8% for nucleoside/nucleotide reverse transcriptase inhibitors, 6.5% for non-nucleoside reverse transcriptase inhibitors and 7.1% for protease inhibitors). Among the 169 naive patients, 75.1%, 10.1% and 7.1% were Italians, South Americans and Romanians, respectively. Heterosexuals were prevalent among Italians and Romanians, while men who have sex with men were predominant among South Americans. The overall frequency of TDR declined from 21.4% to 7.1% in the 1998-2009 period. Although no statistical difference was detected, the frequency of TDR was higher in South Americans (23.5%) compared with Italian and Romanian naive patients (15% and 8.3%, respectively). DISCUSSION: Our study shows a remarkable frequency of TDR in the F1 subtype-infected population. The high prevalence of TDR detected in South American subjects is linked to the homosexual route of infection. However, TDR was considerably high also in Italian subjects harbouring the F1 subtype, deserving careful monitoring.

Interpretation of genotypic resistance to predict darunavir/ritonavir failure in antiretroviral experienced patients.

From the Italian Antiretroviral Resistance Cohort Analysis database, 1104 patients starting ritonavir-boosted darunavir-containing regimen were included as follows: 118 subsequently failed treatment at a median of 11 months (interquartile range: 5-20); 3 years failure proportion: 24.6%. HIV Drug Resistance Database and ANRS interpretation algorithms were associated with a progressive risk prediction of virological failure at adjusted Cox. In contrast, Rega algorithm allows to identify a higher number of patients at risk of failure, without losing statistical significance. Four mutations (V32I, I50V, L76V, I84V) were predictive of failure, the hazard ratio progressively increased by detecting 1 (hazard ratio: 2.0, 95% confidence interval: 1.3 to 3.0), 2 (3.6, 2.0 to 6.6), or 3 of them (9.7, 2.8 to 33.5).

No pol mutation is associated independently with the lack of immune recovery in patients infected with HIV and failing antiretroviral therapy.

An investigation was undertaken to determine whether specific pol mutations hinder long-term immune recovery regardless of virological response. In total, 826 patients with >50 HIV RNA copies/ml, who underwent genotypic resistance testing between 1 January 2000 and 31 December 2003 after >3 years of antiretroviral treatment, and were followed up for >3 years after genotypic resistance testing, were analyzed retrospectively. The outcome of the study was the lack of immune recovery after >3 years of follow-up, defined as a slope by linear regression <0. The viremia detectability ratio was defined as the number of HIV RNA values of >50 copies/ml divided by the number of HIV RNA measurements during follow-up. Logistic regression was used for univariable and multivariable analysis. Median (Q1, Q3) values at baseline were the following: age 40 (37, 45) years, years on antiretroviral therapy 4.45 (3.65, 5.47), HIV RNA 3.91 (3.39, 4.53) log(10) copies/ml, CD4+ T-cell 358 (211, 524)/µl. After 3.13 years of follow-up, 375 patients (45.4%) showed a lack of immune recovery. The risk of lack of immune recovery increased independently with increasing baseline CD4+ counts (OR=1.104 per 50-cell increase, 95% CI=1.069-1.142, P<0.0001), increasing viremia detectability ratio during follow-up (OR=1.145 per 0.1-unit increase, 95% CI=1.093-1.202, P<0.0001), and with earlier calendar years of resistance testing (overall effect: P=0.0007). In conclusion, no pol mutation is associated independently with the lack of immune recovery.

Low rate of virological failure and maintenance of susceptibility to HIV-1 protease inhibitors with first-line lopinavir/ritonavir-based antiretroviral treatment in clinical practice.

Protease inhibitor (PI)-resistant HIV-1 has hardly ever been detected at failed boosted PI-based first-line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first-line lopinavir/ritonavir (LPV/rtv)-based therapy with available baseline HIV-1 RNA load, a viral genotype and follow-up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV-1 RNA >500 and >50 copies/ml, respectively, after 6 months of treatment. Cox proportional hazard models detected baseline HIV-1 RNA (RH 1.79, 95%CI 1.10-2.92 per 1-log(10) increase, P=0.02) and resistance to the nucleoside backbone (RH 1.04, 95%CI 1.02-1.06 per 10-point increase using the Stanford HIVdb algorithm, P<0.001) as independent predictors of HIV-1 RNA at >500 copies/ml, but not at the >50 copies/ml cutoff criteria. Higher baseline viral load, older patient age, heterosexual route of infection and use of tenofovir/emtricitabine were predictors of failure at month 3 using the 50-copy and/or 500-copy threshold. Resistance to LPV/rtv did not occur or increase in any of the available 36 follow-up HIV-1 genotypes. Resistance to the nucleoside backbone (M184V) developed in four cases. Despite the likely differences in patient population and adherence, both the low rate of virological failure and the lack of development of LPV/rtv resistance documented in clinical trials are thus confirmed in clinical practice.

Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy.

BACKGROUND: This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA). METHODS: Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure. RESULTS: The overall resistance prevalence was 81%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) declined after 2002 (68% in 2006; chi(2) for trend P=0.004); resistance to non-NRTIs (NNRTIs) stabilized after 2004; and resistance to protease inhibitors (PIs) declined after 2001 (43% in 2006; P=0.004). In first-line failures, NRTI resistance decreased after 2002 (P=0.006), NNRTI resistance decreased after 2003 (P=0.001) and PI resistance decreased after 2001 (P<0.001). Independent predictors of resistance to any class were HIV type-1 transmission by heterosexual contacts as compared with injecting drug use, a higher number of experienced regimens, prior history of suboptimal therapy, higher viral load and CD4+ T-cell counts, more recent calendar year and viral subtype B carriage, whereas the use of PI-based versus NNRTI-based regimens at failure was associated with a reduced risk of resistance. There was an increase of type-1 thymidine analogue and of protease mutations L33F, I47A/V, I50V and I54L/M, whereas L90M decreased over calendar years. CONCLUSIONS: During more recent years, emerging drug resistance has decreased, particularly in first-line failures. The prevalence continues to be high in multiregimen-failing patients.

Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy.

We investigated, in patients tested between 1991 and 2004, the patterns of mutually exclusive human immunodeficiency virus-1 thymidine-analogue mutations (TAMs) in 4039 reverse-transcriptase sequences with > or = 1 TAM. TAM pattern 1, which included M41L and L210W and excluded K70R and is coupled with more-extensive cross-resistance to drugs, became the most frequent pattern after 1996. In 1465 genotypes from 684 patients in whom highly active antiretroviral therapy (HAART) was unsuccessful, predictors of this pattern were the number of previous HAART regimens undergone (adjusted odds ratio [OR], 1.09 [95% confidence interval {CI}, 1.02-1.16]), use of stavudine/lamivudine (adjusted OR, 1.42 [95% CI, 1.05-1.99]), use of nevirapine (adjusted OR, 1.60 [95% CI, 1.14-2.24]), use of efavirenz (adjusted OR, 1.56 [95% CI, 1.08-2.27]), and use of ritonavir (adjusted OR, 1.35 [95% CI, 1.04-1.75]).