Improving the continuum of care monitoring in Brazilian HIV healthcare services: An implementation science approach.

OBJECTIVE: To evaluate the impact of an intervention improving the continuum of care monitoring (CCM) within HIV public healthcare services in São Paulo, Brazil, and implementing a clinical monitoring system. This system identified three patient groups prioritized for additional care engagement: (1) individuals diagnosed with HIV, but not receiving treatment (the treatment gap group); (2) individuals receiving treatment for >6 months with a detectable viral load (the virologic failure group); and (3) patients lost to follow-up (LTFU). METHODS: The implementation strategies included three training sessions, covering system logistics, case discussions, and development of maintenance goals. These strategies were conducted within 30 HIV public healthcare services (May 2019 to April 2020). After each training session, professionals shared their experiences with CCM at regional meetings. Before and after the intervention, providers were invited to answer 23 items from the normalization process theory questionnaire (online) to understand contextual factors. The mean item scores were compared using the Mann-Whitney U test. The RE-AIM implementation science framework (evaluating reach, effectiveness, adoption, implementation, and maintenance) was used to evaluate the integration of the CCM. RESULTS: In the study, 47 (19.3%) of 243 patients with a treatment gap initiated treatment, 456 (49.1%) of 928 patients with virologic failure achieved suppression, and 700 of 1552 (45.1%) LTFU patients restarted treatment. Strategies for the search and reengagement of patients were developed and shared. Providers recognized the positive effects of CCM on their work and how it modified existing activities (3.7 vs. 4.4, p<0.0001, and 3.9 vs. 4.1, p<0.05); 27 (90%) centers developed plans to sustain routine CCM. CONCLUSION: Implementing CCM helped identify patients requiring more intensive attention. This intervention led to changes in providers' perceptions of CCM and care and management processes, which increased the number of patients engaged across the care continuum and improved outcomes.

Tipranavir/Ritonavir (500/200 mg and 500/100 mg) Was Virologically Non-Inferior to Lopinavir/Ritonavir (400/100 mg) at Week 48 in Treatment-Naïve HIV-1-Infected Patients: A Randomized, Multinational, Multicenter Trial.

Ritonavir-boosted tipranavir (TPV/r) was evaluated as initial therapy in treatment-naïve HIV-1-infected patients because of its potency, unique resistance profile, and high genetic barrier. Trial 1182.33, an open-label, randomized trial, compared two TPV/r dose combinations versus ritonavir-boosted lopinavir (LPV/r). Eligible adults, who had no prior antiretroviral therapy were randomized to twice daily (BID) 500/100 mg TPV/r, 500/200 mg TPV/r, or 400/100 mg LPV/r. Each treatment group also received Tenofovir 300 mg + Lamivudine 300 mg QD. The primary endpoint was a confirmed viral load (VL) <50 copies/mL at week 48 without prior antiretroviral regimen changes. Primary analyses examined CD4-adjusted response rates for non-inferiority, using a 15% non-inferiority margin. At week 48, VL<50 copies/mL was 68.4%, 69.9%, and 72.4% in TPV/r100, TPV/r200, and LPV/r groups, respectively, and TPV/r groups showed non-inferiority to LPV/r. Discontinuation due to adverse events was higher in TPV/r100 (10.3%) and TPV/r200 (15.3%) recipients versus LPV/r (3.2%) recipients. The frequency of grade ≥3 transaminase elevations was higher in the TPV/r200 group than the other groups, leading to closure of this group. However, upon continued treatment or following re-introduction after treatment interruption, transaminase elevations returned to grade ≤2 in >65% of patients receiving either TPV/r200 or TPV/r100. The trial was subsequently discontinued; primary objectives were achieved and continuing TPV/r100 was less tolerable than standard of care for initial highly active antiretroviral therapy. All treatment groups had similar 48-week treatment responses. TPV/r100 and TPV/r200 regimens resulted in sustained treatment responses, which were non-inferior to LPV/r at 48 weeks. When compared with the LPV/r regimen and examined in the light of more current regimens, these TPV/r regimens do not appear to be the best options for treatment-naïve patients based on their safety profiles.

Similar safety and efficacy of once- and twice-daily lopinavir/ritonavir tablets in treatment-experienced HIV-1-infected subjects at 48 weeks.

OBJECTIVES: To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-experienced subjects. METHODS: Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed. RESULTS: Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups. CONCLUSION: LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.

Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials.

BACKGROUND: To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy. METHODS: The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729. FINDINGS: 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group. INTERPRETATION: Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir. FUNDING: Merck.

Primary antiretroviral drug resistance among HIV type 1-infected individuals in Brazil.

Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. The prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. Of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. The prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. The frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014]. Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are already on antiretroviral therapy.

Risk-based assessment does not distinguish between recent and chronic HIV-1 infection in Rio de Janeiro, Brazil

This study investigated the risk factors associated with recent and chronic HIV infections among individual attending a voluntary counseling and testing (VCT) site in Rio de Janeiro, Brazil. In a cross-sectional study, recent HIV infections were detected by the sensitive/less-sensitive test, using Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) strategy, and compared to chronic HIV infection and HIV negative individuals. Seroincidence was estimated and risk factors associated with recent and chronic infections were assessed using multinomial logistic regression. Among the 7,379 individuals tested between June 2006 and April 2007, the overall prevalence and incidence of HIV infection were 7.5 percent; and 1.39/100 PY, respectively. In multivariate analysis, having a HIV positive steady partner was a risk factor for recent and for chronic HIV infection for MSM, heterosexual male and women. No differences in risk factors for recent and chronic infections were found between MSM and heterosexual males. Among women, chronic infected individuals were more likely than HIV negatives to be older. Recently HIV infected women were more likely than HIV negatives to be less educated; and more likely than HIV negatives and chronically infected to report having more partners. Routinely used risk-based assessment in testing centers in Brazil lack sensitivity to distinguish between recent and chronic infections, particularly among MSM and heterosexual males. Steady relationships and serosorting may be playing a key role in maintaining the HIV epidemics in Brazil.

Monotherapy with Lopinavir/Ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMo study).

BACKGROUND: Long-term adverse events and expenses associated with HAART have led to an interest in simplified therapy. Lopinavir/ritonavir monotherapy is attractive due to its potency and high genetic barrier. METHODS: This is a 96-week, open-label, randomized study to assess the feasibility of using LPV/r monotherapy in patients with undetectable viral load after being on successful HAART for at least 6 months. Subjects were randomized (1:1) to either switch from HAART to LPV/r monotherapy or to maintain their previous regimen. RESULTS: 60 patients were enrolled. Baseline characteristics were similar in both groups. At Week 96, by intention-to-treat analysis, 24/30 (80.0%) subjects in monotherapy group and 26/30(86.6%) in the control group had a plasma viral load of <80 copies/mL. There was one virologic failure (defined as VL not greater-than 500 copies/mL) in each arm. Genotyping testing identified no resistance-associated mutations. The patient on the monotherapy arm was successfully resuppressed to <80 copies/mL after intensification with tenofovir and lamivudine. No statistically significant differences were found with regard to changes in CD4 counts. One subject in the monotherapy group discontinued due to diarrhea. Five subjects in the control group underwent regimen changes due to drug-related toxicities. Viral load from semen samples collected at the end of follow-up was undetectable on 14/15 patients randomized to monotherapy. CONCLUSIONS: Switching from various HAART regimens to LPV/r monotherapy in patients who were virologically suppressed and without a history of previous virologic failure was effective, safe, and well tolerated through 96 weeks.

Risk-based assessment does not distinguish between recent and chronic HIV-1 infection in Rio de Janeiro, Brazil.

This study investigated the risk factors associated with recent and chronic HIV infections among individual attending a voluntary counseling and testing (VCT) site in Rio de Janeiro, Brazil. In a cross-sectional study, recent HIV infections were detected by the sensitive/less-sensitive test, using Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) strategy, and compared to chronic HIV infection and HIV negative individuals. Seroincidence was estimated and risk factors associated with recent and chronic infections were assessed using multinomial logistic regression. Among the 7,379 individuals tested between June 2006 and April 2007, the overall prevalence and incidence of HIV infection were 7.5%; and 1.39/100 PY, respectively. In multivariate analysis, having a HIV positive steady partner was a risk factor for recent and for chronic HIV infection for MSM, heterosexual male and women. No differences in risk factors for recent and chronic infections were found between MSM and heterosexual males. Among women, chronic infected individuals were more likely than HIV negatives to be older. Recently HIV infected women were more likely than HIV negatives to be less educated; and more likely than HIV negatives and chronically infected to report having more partners. Routinely used risk-based assessment in testing centers in Brazil lack sensitivity to distinguish between recent and chronic infections, particularly among MSM and heterosexual males. Steady relationships and serosorting may be playing a key role in maintaining the HIV epidemics in Brazil.

Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults.

OBJECTIVES: Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels. DESIGN: 48-week substudy of a randomized, open-label, three-arm trial. SETTING: Hospital and community HIV clinics. PARTICIPANTS: 140 HIV-infected adults naive to antiretroviral therapy. INTERVENTION: Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine. MAIN OUTCOME MEASURES: Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r. RESULTS: Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml). CONCLUSION: Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Health-related quality of life outcomes in HIV-infected patients starting different combination regimens in a randomized multinational trial: the INITIO-QoL substudy.

The health-related quality of life (HRQoL) outcomes in HIV-infected, treatment-naive patients starting different HAART regimens in a 3-year, randomized, multinational trial were compared. HRQoL was measured in a subgroup of patients enrolled in the INITIO study (153/911), using a modified version of the MOS-HIV questionnaire. The regimens compared in the INITIO trial were composed by two NRTIs (didanosine + stavudine) plus either an NNRTI (efavirenz) or a PI (nelfinavir), or both (efavirenz + nelfinavir). Primary HRQoL outcomes were Physical and Mental Health Summary scores (PHS and MHS, respectively). During follow-up, an increase of PHS score was observed in all treatment arms. The MHS score remained substantially unchanged with the four-drug combination and showed with both NNRTI- and PI-based three-drug regimens a marked trend toward improvement, which became statistically significant when a multiple imputation method was used to adjust for missing data. Overall, starting all the combination regimens compared in the INITIO study was associated with a maintained or slightly improved HRQOL status, consistently with the positive immunological and virological changes observed in the main study. The observed differences in the MHS indicate a possible HRQoL benefit associated to the use of three-drug, two-class regimens and no additional benefit for the use of four-drug, three-class regimens, confirming that three-drug, two-class regimens that include two NRTIs plus either an NNRTI or a PI should be preferred as initial treatment of HIV infection.

Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts.

RATIONALE: Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies. OBJECTIVES: To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil. METHODS: Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr. MEASUREMENTS: TB rates, adverse events, and adherence to therapy. MAIN RESULTS: A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%). CONCLUSIONS: Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection.