E. H. Gisolf

Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection.

BackgroundChanges in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly. MethodThe occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study). ResultsLipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008). ConclusionThis randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.

Predictors and correlates of adherence to combination antiretroviral therapy (ART) for chronic HIV infection: a meta-analysis

BackgroundAdherence to combination antiretroviral therapy (ART) is a key predictor of the success of human immunodeficiency virus (HIV) treatment, and is potentially amenable to intervention. Insight into predictors or correlates of non-adherence to ART may help guide targets for the development of adherence-enhancing interventions. Our objective was to review evidence on predictors/correlates of adherence to ART, and to aggregate findings into quantitative estimates of their impact on adherence.MethodsWe searched PubMed for original English-language papers, published between 1996 and June 2014, and the reference lists of all relevant articles found. Studies reporting on predictors/correlates of adherence of adults prescribed ART for chronic HIV infection were included without restriction to adherence assessment method, study design or geographical location. Two researchers independently extracted the data from the same papers. Random effects models with inverse variance weights were used to aggregate findings into pooled effects estimates with 95% confidence intervals. The standardized mean difference (SMD) was used as the common effect size. The impact of study design features (adherence assessment method, study design, and the United Nations Human Development Index (HDI) of the country in which the study was set) was investigated using categorical mixed effects meta-regression.ResultsIn total, 207 studies were included. The following predictors/correlates were most strongly associated with adherence: adherence self-efficacy (SMD = 0.603, P = 0.001), current substance use (SMD = -0.395, P = 0.001), concerns about ART (SMD = -0.388, P = 0.001), beliefs about the necessity/utility of ART (SMD = 0.357, P = 0.001), trust/satisfaction with the HIV care provider (SMD = 0.377, P = 0.001), depressive symptoms (SMD = -0.305, P = 0.001), stigma about HIV (SMD = -0.282, P = 0.001), and social support (SMD = 0.237, P = 0.001). Smaller but significant associations were observed for the following being prescribed a protease inhibitor-containing regimen (SMD = -0.196, P = 0.001), daily dosing frequency (SMD = -0.193, P = 0.001), financial constraints (SMD -0.187, P = 0.001) and pill burden (SMD = -0.124, P = 0.001). Higher trust/satisfaction with the HIV care provider, a lower daily dosing frequency, and fewer depressive symptoms were more strongly related with higher adherence in low and medium HDI countries than in high HDI countries.ConclusionsThese findings suggest that adherence-enhancing interventions should particularly target psychological factors such as self-efficacy and concerns/beliefs about the efficacy and safety of ART. Moreover, these findings suggest that simplification of regimens might have smaller but significant effects.

Risk Factors for Hepatotoxicity in HIV-1—Infected Patients Receiving Ritonavir and Saquinavir with or without Stavudine

Liver enzyme elevation (LEE) is commonly observed after combination antiretroviral therapy (ARVT) for HIV infection is begun. Potential risk factors for LEE after treatment with ritonavir and saquinavir with or without stavudine were investigated in 208 HIV-infected patients, by use of the Cox proportional hazard model. Eighteen patients (9%) developed LEE during the 48-week follow-up. Multivariate analysis, adjusted for baseline levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), showed that hepatitis B surface antigen (HBsAg) positivity (relative risk [RR], 8.8; 95% confidence interval [CI], 3.3-23.1) and the use of stavudine (RR, 4.9; 95% CI, 1.5-16.0) were the only significant risk factors for developing LEE. After LEE occurred, ALT and AST concentrations decreased by >50% in 13 of 14 patients who continued ARVT during LEE. In this study, it appeared safe to continue ARVT during LEE; however, more data from larger studies are required to confirm this finding.

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

ObjectiveTo assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1-infected patients. DesignA multicentre, open-label, randomized controlled trial. MethodsA total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. ResultsThe median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. ConclusionRTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir.

ObjectiveTo explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir. MethodsThe pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily. ResultsThe first study day was 4–12 months (median 7 months) after the start of the current regimen. The second study day was 9–15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was −30% (range −79 to +11%;P = 0.06). Median change in maximum plasma concentration was −40% (range −62 to +34%;P = 0.09). The median change in area under the plasma concentration versus time curve over 0–8 h was −33% (range −53 to +21%;P = 0.06). ConclusionThe exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients.

The effect of treatment intensification in HIV-infection : A study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine

ObjectiveTo evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/stavudine (D4T) or RTV/SQV alone, with treatment intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. DesignMulticentre, open-label, randomized controlled trial. Two-hundred and eight patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks. ResultsIn a strict intention-to-treat analysis, counting all dropouts as virological failures, 63% [95% confidence interval (CI), 54–73%] of subjects in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week 48, as compared with 69% (95% CI, 60–78%) in the RTV/SQV/D4T group (n = 104;P = 0.379). In the on-treatment analysis these percentages were 88 and 91% respectively. Thirty-one patients intensified their study medication according to the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events. ConclusionThe concept of starting with a simple, potent regimen, that could be intensified if necessary, showed good virological results after 48 weeks in this study, comparable to starting with more drugs from the beginning. Longer follow-up is needed to determine the long-term efficacy of this treatment strategy.

Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy.

&NA;Only limited data on cerebrospinal fluid (CSF) HIV‐1 RNA responses and markers of local inflammation in CSF during antiretroviral therapy are available. HIV‐RNA, soluble tumor necrosis factor (TNF)‐receptor (sTNFr)‐II, monocyte chemoattractant protein (MCP)‐1, and interferon‐&ggr;‐inducible protein (IP)‐10 were measured in the peripheral blood and CSF of 26 antiretroviral‐naive HIV‐1‐positive patients, who were treated with ritonavir (RTV)/saquinavir (SQV) (n = 5), RTV/SQV/ stavudine (d4T; n = 8) or zidovudine (AZT)/lamivudine (3TC)/abacavir/nevirapine/indinavir (n = 13). After 8 to 12 weeks of treatment, CSF HIV‐RNA dropped to <400 copies/ml in 1 of 5 patients in the RTV/SQV group, 8 of 8 patients in the RTV/SQV/d4T group, and 9 of 10 patients in the five‐drug group. CSF sTNFr‐II and IP‐10 levels increased in patients with detectable CSF HIV‐RNA. However, increases in CSF chemokine and sTNFr‐II concentrations were also observed in some patients with good CSF HIV‐RNA responses. Moreover, CSF MCP‐1 concentrations increased in the whole population after 2 months of treatment. Ongoing residual HIV replication in the central nervous system, which cannot be detected with CSF HIV‐RNA measurements, may account for this phenomenon.

Changes in hematological parameters after switching treatment of HIV-infected patients from zidovudine to abacavir or tenofovir DF.

Purpose of the study Administration of zidovudine (AZT) to patients infected with the Human Immunodeficiency Virus (HIV) is associated with anemia and leukopenia. The presence of anemia is correlated with quality of life and mortality in HIVinfected patients. Our objective was to investigate the effect of switching from AZT to alternative antiretroviral therapy on hematological parameters in HIV-infected patients.

A systematic review of a single-class maintenance strategy with nucleoside/nucleotide reverse transcriptase inhibitors in HIV/AIDS.

BACKGROUND Single-drug class regimens with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are generally not recommended as initial therapy because they are inferior compared with therapy with two NRTIs plus efavirenz. However, triple-NRTI combinations can be useful in specific circumstances such as in tuberculosis coinfection, pregnancy or dyslipidaemia. Here, we review the potential of such combinations to maintain viral suppression after induction of suppression by standard combination antiretroviral therapy (cART) and to evaluate the trade-off of NRTI-only regimens for metabolic control. METHODS We conducted a systematic search of the literature in two databases from 1 January 1998 up to 1 March 2013: Medline, through the search engine PubMed, and Embase. RESULTS A total of 11 randomized controlled trials (RCTs) with 2,105 patients and 3 observational studies with 2,639 patients were included. Studies including patients with mono- or dual-NRTI treatment before start of effective cART showed a tendency to higher failure rate because of resistance based on archived viral mutations. In studies with ART-naive subjects before start of cART, triple-NRTI combination showed virological activity comparable to two NRTIs plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor in all RCTs, but not in one cohort study. Switching improved serum lipids significantly. CONCLUSIONS Of the studied triple-NRTI combinations only abacavir/lamivudine/zidovudine was sufficiently potent. Triple-NRTI maintenance after successful induction with two-class cART appeared successful in treatment-naive subjects and remains a useful option in specific circumstances, especially when other drugs are not available or drug interactions are an issue.

Overcoming Outpatient Loss to Follow-up as a Barrier to Efficiently Instituting Hepatitis B Liver-related Care

Clinical Infectious Diseases 2017;64(2):232–33 Also, frequently no information beyond histopathology is available because no cultures from the biopsy material were sent due to low suspicion of an infection. The recently released, comprehensive Coccidioidomycosis guidelines [3] do not directly address what strategy or strategies are to be considered in this situation. Realizing the available quality of evidence is very low, I suggest that these asymptomatic patients be treated with an oral azole-based regimen for at least 3 months followed by close monitoring. For patients with high risk for an opportunistic mold infection, such as hematologic malignancy or allogeneic transplant, perhaps a mold-active azole is preferable to fluconazole, especially in the setting of a cavitating Coccidioidal nodule, where secondary colonization by another mold (eg, Aspergillus) could occur. I offer the following rationale for supporting a trial of “preemptive” azole treatment. First, there is, although unmeasured, risk for progression or dissemination of this occult lung infection in the setting of subsequent immune impairment [2, 4], and there are no clinical or immunogenetic predictors to prognosticate this event. Second, the possibility of extrapulmonary Coccidioidal lesions beyond the dominant Coccidioidal nodule exists; therefore, the burden of fungal disease might be underestimated by conventional computerized tomography of the lung. As Coccidioidal lesions are F-Fluorodeoxyglucose-avid [5] and in view of the well-known poor sensitivity of Coccidioides serology in immunosuppressed patients [2], positron emission tomography /computed tomography as a baseline to look for the extent of lung involvement and to evaluate for cryptogenic disseminated diseases [6] could be informative in selected cases. Third, as pulmonary Coccidioidal lung nodules simulate cancer [1, 2], it would be important in a patient with underlying cancer and an asymptomatic pulmonary Coccidioidal nodule to eradicate these nodules with antifungals. This can facilitate the downstream differential diagnosis in case the patient subsequently develops new pulmonary lesions. In view of the availability of oral azoles that have excellent efficacy and long-term safety, the benefit of treating preemptively far outweighs the risk. Finally, surgical resection can be an alternative modality in selected patients with solitary culture-proven Coccidioidal cavitating lung nodule, if no further chemotherapy is planned and azole treatment is not feasible or is undesirable. Again, more studies are needed in order to validate this proposed strategy. I thank Galgiani et al for their significant contribution with their guidelines to the clinical management of a complex disease.