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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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HIV at ICAAC Comorbidities 2013
  (Sept 10-13, Denver, CO) (Sept 10-13, Denver, CO)
Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
Comorbidities. Improvements in the safety, tolerability, potency and ease of use of antiretroviral therapy has allowed most patients with HIV to achieve durable viral suppression and remain stable on antiretroviral therapy (ART) for years. As a result, management of the many non-AIDS comorbidities that occur in HIV-positive individuals now consumes a large a part of any HIV care providers effort. New studies on the management of comorbidities, including osteoporosis, cancer, cardiovascular disease, and liver disease was presented at ICAAC 2013. Osteoporosis is increased in HIV-infected individuals. Traditional risk factors, HIV-infection itself and ART all may contribute to the pathogenesis of this condition. Most previous studies have shown that bone mineral density (BMD) declines during the first 6-18 months on ART, then stabilizes. The magnitude of decline may be affected by the specific components of the regimen. With use of tenofovir DF (TDF) or protease inhibitors, BMD declines are usually greater. Two studies presented at ICAAC 2013 compared the bone effects of TDF/emtricitabine (FTC) with abacavir/lamivudine (ABC/3TC) using serum markers of bone turnover rather than direct measurement of bone mineral density (BMD). The SINGLE trial was a large, randomized, double blind comparison of the regimen ABC/3TC plus the integrase inhibitor dolutegravir and coformulated TDF/FTC/efavirenz (EFV).
Analysis of the primary safety and efficacy endpoints have been presented elsewhere. At 48 weeks, the bone resorption marker C-telopeptide (CTx) and the markers of new bone formation osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and procollagen type 1 N-terminal propeptide (P1NP) all increased, but the increases were significantly greater in the TDF/FTC/EFV arm [1]. Vitamin D levels also were measured and did not differ between arms. The ASSURE study [2] enrolled patients stably suppressed on a first or second ART regimen consisting of TDF/FTC plus ritonavir-boosted atazanavir and no history of virologic failure. Participants were randomized 2:1 to switch to open-label ABC/3TC/atazanavir without boosting or to continue the baseline regimen. At 48 weeks, 77% and 81% of subjects in the switch and control groups, respectively, maintained an HIV RNA <50 copies/mL, a statistically non-significant difference (FDA snapshot analysis). Three bone turnover markers, BSAP, CTx, OC declined at weeks 24 and 48 in the switch group, while all remained stable in the control group. PTH also declined in the switch arm, although serum calcium was unchanged. The differences in marker levels between arms at week 48 were statistically significant. Other study findings included no clinically significant differences in lipid profile, and no differences in estimated GFR or the inflammatory markers hsCRP, IL-6 or d-dimer. There were also no differences in adverse events or laboratory toxicities, except for the expected higher rate of hyperbilirubinemia in the control arm that used ritonavir boosted atazanavir.
These findings are consistent with previous studies that used DEXA to demonstrate a greater loss of BMD with TDF/FTC containing ART. The SINGLE study findings suggest the inclusion of the new integrase inhibitor dolutegravir does not alter the effect on bone. However, unlike BMD measurement, the clinical significance of changes in bone turnover markers and their ability to predict risk for clinical events such as fracture has not been established. In the absence of correlation between bone turnover markers and fractures, studies directly measuring BMD will have greater clinical relevance.
Cancer. In the era of effective ART, cancer is among the leading causes of death in HIV-infected individuals. Classical AIDS-related cancers have declined but continue to occur in patients who are untreated or incompletely treated. Rates of certain non-AIDS cancers appear to be increased in HIV. With concurrent use of ART to suppress HIV replication and improve host immune function, treatment of many cancers in HIV-infected individuals can be as effective as in HIV-negative patients. However, finding an effective ART regimen to combine with cancer chemotherapy may be challenging. Because of a favorable safety and tolerability profile, and freedom from major drug-drug interactions, the integrase strand transfer inhibitor (INSTI) raltegravir is preferred by many experts to anchor ART regimens in patients receiving cancer chemotherapy. Investigators from the MD Anderson Cancer Center retrospectively reviewed their experience with ART use and outcome in 154 HIV-infected patients treated for cancer between 2001-2102 [3]. The majority had hematologic malignancies, mostly lymphoma. Outcomes were analyzed in four ART groups; 2 NRTIs plus either a protease inhibitor (n=57), an NNRTI (n=50), an INSTI (n=30), and other combinations (n=17). Viral efficacy was defined as maintaining HIV RNA <200 copies/mL, or absence of rebound to >200 after reaching <200, and was assessed after 6 months of treatment. In a multivariable analysis, the INSTI or NNRTI groups were 6 and 9 times more likely to have virologic success, respectively, than those in the PI group. Mortality, treatment interruptions and ART-related adverse events were lower in the INSTI group (13/7/3%, respectively) than either the NNRTI (36/26/14/%) or the PI (46/28/35%) group. The study has several limitations, including retrospective data collection, non-random assignment to treatment, small sample size and differences in baseline characteristics among ART groups. Because clinicians often choose ART-regimens based on patient characteristics, channeling bias may have influenced the observed outcomes. Nevertheless, this study provides support for the practice of choosing the INSTI raltegravir, to anchor ART regimens. Raltegravir was the only INSTI used during this study. Because elvitegravir and dolutegravir have different safety and drug interaction profiles, the observations in this study probably should not be extrapolated to these newer INSTIs.
Cardiovascular Disease (CVD). CVD, including MI and stroke, is one of the three leading non-AIDS-related causes of death in HIV-infected individuals. Despite metabolic disturbances associated with certain antiretrovirals, ART reduces overall CVD risk, presumably by reducing the chronic immune activation and inflammation present in untreated HIV. Management of CVD in HIV is complicated by the metabolic effects of ART, drug-drug interactions, and the possibility that a different balance of pathogenic factors may require different therapies. For individuals in the general population both statins and aspirin are effective for primary and secondary CVD prevention. Although there is little efficacy data in the HIV population, most experts believe statins and ASA should be used for the same indications as in the general population.
Park et al. retrospectively reviewed aspirin and statin use among patients seen at an HIV specialty clinic during 2012 [4]. Patients were included if they had no history of stroke or MI, no contraindication to aspirin and were within the age range specified by the USPSTF for consideration of primary prophylaxis with aspirin. Risk of MI was assessed using both the Framingham and DAD systems. Risk of stroke was assessed by the Framingham system. Half of the 258 patients analyzed were at sufficiently increased risk of MI to warrant aspirin prophylaxis, but only 43% of the high risk group were using it. Fourteen percent were at increased risk of stroke, and only half were using aspirin. Statins also appeared to be underutilized, but since the patient population was selected to analyze the appropriateness of primary aspirin prophylaxis, conclusions about statin use were less clear. The study suggests aspirin is underutilized for primary prevention of both MI and stroke in HIV. Increased provider education and clinical trials demonstrating efficacy in HIV-infected patients may help increase utilization.
Use of statins in HIV is complicated by many drug-drug interactions with ARVs, mostly because of the effects of commonly used ARVs on CYP450 metabolic pathways. Pitavastatin is a potent member of the statin class that is metabolized primarily by glucuronidation. Malvestutto et al [5] investigated the pharmacokinetic (PK) interactions between pitavastatin and two commonly used ARVs that interact with multiple other statins. In healthy volunteers, neither efavirenz nor ritonavir-boosted darunavir coadministration significantly altered pitavastatin PK. Levels of the ARVs also were unaltered by coadministration. Although interaction studies with other ARVs will be needed, this study suggests pitavastatin may be useful in the management of CVD risk in HIV-infected individuals. However, no generic formulation is available, so access for some patients may be limited by insurers.
Liver Disease. Liver disease is a common comorbidity that is among the leading causes of death in HIV. It results predominantly from complications of HCV infection. Following antiviral treatment of HCV, a sustained virologic response (SVR), has been shown to reduce liver-related clinical events and all cause mortality in both HCV mono-infected and HIV/HCV co-infected patients. Current treatment is arduous and is often deferred in patients with milder degrees of liver fibrosis. However, HCV treatment is undergoing rapid advances. In the near future it should be possible to cure most patients with shorter and better tolerated, but also very expensive antiviral regimens. Therefore, it is important to identify the optimal time to treat HCV in co-infected patients. Berenguer et al reviewed the clinical outcome in 695 HIV/HCV co-infected patients with non-advanced liver fibrosis (Metavir F0, 1, 2) who were treated with ribavirin plus interferon between 2000-2008 at 19 centers in Spain [6]. Thirty-five percent achieved an SVR. As would be expected, SVR patients had lower baseline HCV RNA, more HCV genotype 2 or 3 infection and less heavy alcohol use than non-SVR patients. During follow-up through July 2010, liver events, liver decompensation, liver-related mortality and all cause mortality were significantly lower in the SVR group. All differences were driven by the subset with F2 fibrosis. Those with F0 and F1 did not benefit significantly. In a multivariable analysis adjusting for age, gender, injection drug use, CD4 counts, CDC class, HCV genotype and baseline HCV RNA, SVR was associated with an 89% decrease in the risk of liver-related events in the F2 group (p=0.035). This study is a cohort analysis in which the assignment to treatment was not randomized. There are likely other differences between patients who do or do not achieve an SVR that were not adjusted for. These differences may confound the results. Nevertheless, the magnitude of the benefit of achieving an SVR for those with F2 fibrosis is large enough that it probably cannot be fully explained by confounding. These findings suggest all patients with HIV/HCV co-infection and F2 or greater fibrosis should be treated for HCV, especially when new treatments that greatly increase the likelihood of SVR become available.
1. Tebas P, Kumar P, Hicks PC, et al. 48 Week Bone Marker Changes with Dolutegravir (DTG; GSK1349572) plus Abacavir/Lamivudine (ABC/3TC) vs. Tenofovir/Emtricitabine/Efavirenz (EFV/TDF/FTC): the SINGLE Trial. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1461.
2. Wohl D, Bhatti L, Small CB et al. Simplification to Abacavir/Lamivudine (ABC/3TC) + Atazanavir (ATV) from Tenofovir/Emtricitabine (TDF/FTC) + ATV/Ritonavir (r) Maintains Viral Suppression and Improves Bone Biomarkers: 48 Week ASSURE Study Results. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-665.
3. Torres HA, Rallapalli V, Saxena A, et al. Efficacy and Safety of Antiretrovirals in HIV-Infected Patients with Cancer. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1255.
4. Park TE, Sharma R, Yusuff J. Use of Aspirin and Statins for the Primary Prevention of Myocardial Infarction and Stroke in Patients with Human Immunodeficiency Virus. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1257.
5. Malvestutto CD, Ma Q, Morse GD,et al. Pharmacokinetic Study Assessing Drug Interactions of Pitavastatin with Darunavir/Ritonavir and Pitavastatin with Efavirenz in Healthy Volunteers. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract A-1577c.
6. Berenguer J, Zamora FX, Diez C, et al. Hepatitis C Eradication Reduces Liver Decompensation, HIV Progression, and Death in HIV/HCV-Coinfected Patients with Non-Advanced Liver Fibrosis. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1527.
ICAAC: 48 Week Bone Marker Changes in Dolutegravir (DTG; GSK1349572) Plus Abacavir/Lamivudine (ABC/3TC) vs Tenofovir/Emtricitabine/Efavirenz (EFV/TDF/FTC): The SINGLE Trial - (09/13/13)
ICAAC: Simplification to Abacavir/Lamivudine (ABC/3TC) + Atazanavir (ATV) From Tenofovir/Emtricitabine (TDF/FTC) + ATV/Ritonavir (r) Maintains Viral Suppression and Improves Bone Biomarkers: 48 Week ASSURE - (09/16/13)
ICAAC: Raltegravir Top PIs and NNRTIs in Retrospective Look at Cancer Patients - Written by Mark Mascolini - (09/14/13)
ICAAC: Hepatitis C Eradication Reduces Liver Decompensation, HIV progression, and Death in HIV/HCV-coinfected Patients with non-Advanced Liver Fibrosis - (09/12/13)
53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 2013, Denver CO