Predicting Long-Term CD4-Cell Counts and Viral Loads

Pretreatment CD4-cell count, age at initiation of therapy, and early treatment response are strong predictors of CD4-cell recovery and virologic suppression 5 to 12 years after ART initiation. Very few studies have examined CD4-cell counts and viral loads in patients on long-term potent antiretroviral therapy (ART). Here, researchers evaluate data from 614 men in the MACS cohort who had been taking ART consistently for 5 to 12 years. At the time of ART initiation, 12% of the men were aged 50 and older, 40% were antiretroviral-naive, and more than 50% had CD4 counts 350 cells/mm3 and viral loads 10,000 copies/mL. After 5 to 12 years of ART, the median CD4 count was 585 cells/mm3, and viral loads were undetectable at 78% of study visits. Multivariate analyses revealed the following: Pretreatment CD4-cell counts 500 cells/mm3 and age 50 at ART initiation were both associated with lower long-term CD4-cell counts. Among patients who were antiretroviral-naive at ART initiation, older men gained an average of 60 fewer CD4 cells/mm3 than younger men. Remaining on the same first or second regimen during the first 5 years of treatment and maintaining virologic suppression for at least half that time were both associated with higher longterm CD4-cell counts. Virologic response during the first 5 years of ART and complete adherence to ART both predicted long-term virologic suppression. Protease inhibitors and nonnucleoside reverse transcriptase inhibitors were equally likely to suppress viral loads and also had similar effects on CD4-cell recovery. Comment: Three main points emerge from this study. First, pretreatment CD4-cell counts predict subsequent counts, even many years later. Second, older age at ART initiation reduces the likelihood of a sustained improvement in CD4-cell counts. Finally, adherence and virologic response predict the durability of a regimen, with the best results observed in patients who are treated successfully on their first or second regimens. In aggregate, these data suggest that initiating ART at an earlier stage of HIV infection, with the most potent regimen that an individual can tolerate and commit to, will provide excellent long-term results especially since all of today's preferred regimens are virtually guaranteed to lead to virologic suppression, provided that adherence is adequate. Sonia Nagy Chimienti, MD Published in Journal Watch HIV/AIDS Clinical Care August 1, 2011

Non-AIDS Events A Major Problem for Patients Receiving ART in Africa

Such events caused 30% of all deaths in a cohort of patients receiving ART in Botswana versus 4% of deaths in a U.S. cohort. In resource-rich countries, nonAIDS-defining events have emerged as the leading cause of morbidity and mortality among HIV-infected patients receiving antiretroviral therapy (ART). Whether such events are also important among patients taking ART in resource-limited settings is unknown. To explore this issue, researchers compared the incidence of nonAIDS-defining events in 20022007 between two cohorts of adults taking ART: an observational cohort in Nashville, Tennessee (n=1129) and a clinical-trial cohort in an urban area of Botswana (n=650). The main criteria for starting ART in Botswana were similar to those in the U.S. at the time. The two cohorts differed significantly with respect to age (median, 33 in the Botswana cohort vs. 40 in the Nashville cohort), sex (69% female vs. 26% female), race (100% African vs. 35% African-American), and baseline CD4 count (199 vs. 243 cells/mm3). Median follow-up was 3 years and 1.5 years, respectively. There were 18 nonAIDS-defining events in the Botswana cohort (2.8%) and 25 in the Nashville cohort (2.2%), yielding crude incidence rates of 10.0 and 12.4 events per 1000 patient-years, respectively. When standardized to the U.S. population (for age and sex), the rates were 18.7 and 12.4 events per 1000 patient-years. The Botswana cohort had higher standardized rates of cardiovascular events and non AIDS-defining malignancies (although only the latter was significant), whereas the Nashville cohort had a higher rate of hepatic events; the incidence of renal events was similar. NonAIDS-defining events were the cause of 30% of all deaths in the Botswana cohort versus 4% of deaths in the Nashville cohort. Comment: Although the observation time in this study was short and the event rates seem low, the results demonstrate the increasing importance of nonAIDS-defining events among HIV-infected patients receiving ART in resource-constrained settings. In these regions, addressing the far-ranging health issues subsumed under the category "nonAIDS-defining events" (i.e., heart and liver disease, cancer) will require effective use of resources already strained by the HIV, malaria, and tuberculosis epidemics. Keith Henry, MD Published in Journal Watch HIV/AIDS Clinical Care August 1, 2011

A Link Between CD4 Nadir and Dementia

The lower the nadir CD4-cell count, the higher the risk for neurocognitive impairment. Researchers have repeatedly demonstrated that HIV-associated neurocognitive impairment can arise or persist in patients who have achieved virologic suppression on antiretroviral therapy (JW AIDS Clin Care Mar 28 2011). What exactly is creating the risk in these patients, if it's not ongoing, uncontrolled systemic HIV replication? A new study points to the nadir CD4-cell count. Among 1525 HIV-infected individuals participating in a multicenter observational study, 799 (52%) were found to have global neuropsychological impairment. Seventy-five percent of these individuals (39% of

the total cohort) had no medical reason for this condition other than HIV infection. Patients with impairment were similar to those without impairment in terms of demographics and current CD4-cell count and viral-load measurements; however, they had a significantly lower median self-reported nadir CD4 count (155 vs. 187 cells/mm3) and were significantly more likely to be taking antiretrovirals (75% vs. 67%). The risk for neurocognitive impairment was found to decrease linearly as the square root of the nadir CD4-cell count rose an association that persisted in multivariate analysis and held true for the impaired group as a whole, for the subset in whom HIV seemed the likely culprit, and for those with laboratory confirmation of nadir CD4-cell counts. Comment: These authors conclude that the earlier individuals are treated for HIV infection, the less likely they are to experience neuropsychological impairment. Given that no clear CD4-cell count threshold emerged from this study (impairment was seen in patients with nadir CD4 counts as high as 277 cells/mm3), the findings provide general support for starting HIV treatment as early as possible. Abigail Zuger, MD Published in Journal Watch HIV/AIDS Clinical Care July 25, 2011

CITATION(S):
Ellis RJ et al. Nadir CD4 is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS2011 Jul 6; [e-pub ahead of print]. (http://dx.doi.org/10.1097/QAD.0b013e32834a40cd)

Viral-Load Monitoring Beneficial in Resource-Constrained Settings

A new study quantifies the benefits of such monitoring but does little to answer the bigger question of whether limited funds should be spent on monitoring or on providing ART to more patients. Millions of HIV-infected people in low-income countries have been placed on antiretroviral therapy (ART) in the past few years, an achievement once considered impossible. Unfortunately, millions more need immediate treatment and do not have access to it, and concerns abound about the lack of viral-load monitoring among those already on treatment. Without such monitoring, patients with undetectable viral loads may be switched to second-line ART unnecessarily, and those with virologic failure may experience a delay in switching that could promote the development of drug resistance, compromise response to subsequent therapy, and influence survival. In the present study, researchers compared outcomes of ART in settings with and without viral-load monitoring. The study involved 18,706 patients starting ART at sites in South Africa, where viral-load monitoring is routinely used, and 80,937 patients starting ART at sites in Malawi and Zambia, where monitoring is based on CD4-cell counts.

At 3 years, all the outcomes evaluated (failure on first-line therapy, switch to second-line therapy, loss to follow-up, and death) were more favorable in patients being followed at sites that routinely monitor viral loads (see table). Importantly, however, the proportion of patients who were known to be alive and on first-line therapy without meeting criteria for failure was comparable between the sites that monitored viral load and those that did not (75.4% and 72.6%, respectively). Comment: Given that funds are (and always will be) limited, health officials face a Sophie's choice: The more they spend on monitoring, the fewer patients that can receive life-saving ART. The rigorous data analysis used in this study, together with the large number of participants, allowed the researchers to estimate, with unprecedented precision, the advantages of viral-load monitoring. However, no one ever disputed the benefit of using this tool. Thus, this study did not address the real issue at hand: For any given amount of available funds, which strategy saves the most lives monitoring patients already on treatment or providing ART to even more patients? Mauro Schechter, MD Dr. Schechter is a Professor of Infectious Diseases at Universidade Federal do Rio de Janeiro, Head of the AIDS Research Laboratory at Hospital Universitario Clementino Fraga Filho, and Principal Investigator of Projeto Praa Onze at Hospital Escola So Francisco de Assis in Brazil. He reports no conflicts of interest. Published in Journal Watch HIV/AIDS Clinical Care July 18, 2011

CITATION(S):
Keiser O et al. Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in Southern Africa. AIDS 2011 Jun 15; [e-pub ahead of print]. (http://dx.doi.org/10.1097/QAD.0b013e328349822f)

Mortality Remains High Among Urban Poor Despite ART Availability

Even with access to free ART and specialty care at a public clinic, 10% of HIV-infected patients with nadir CD4 counts 350 cells/mm3 died during a 4-year period. Widespread use of potent antiretroviral therapy (ART) has resulted in impressive population-wide declines in HIV-related morbidity and mortality. But do these benefits extend to disadvantaged, urban HIV-infected populations in the U.S.? Investigators evaluated mortality rates among 1651 HIV-infected adults in San Francisco who had nadir CD4 counts 350 cells/mm3 and were seen at least twice within 1 year, between 2000 and 2009, at a

public HIV clinic that offered universal access to ART. The study population was 87% men and 47% white. At study entry (usually the patient's second clinic visit), patients had a median age of 49, a median CD4 count of 205 cells/mm3, and a median viral load of 35,000 copies/mL; ART had been prescribed for 41% (vs. 78% by the end of the study). Comorbidity rates were high: 31% of patients were hepatitis C virus (HCV)-positive, 40% had documented mental illness, and 10% had a history of alcohol abuse. A total of 172 patients (10%) died during a median 3.7 years of follow-up. (The mean all-cause mortality rate was 2.7% annually, with no change observed over time.) Most of the deaths (56%) were AIDS related, although a substantial proportion was due to violence/drug overdose (including suicide) and smoking-related diseases (16% and 6%, respectively). Among the patients who died, only 42% had achieved virologic suppression (<400 copies/mL) during the study, and the median CD4 count had remained virtually unchanged (128 cells/mm3 at baseline and 101 cells/mm3 at last measurement). In contrast, among the patients who survived, 69% achieved virologic suppression, and the median CD4 count improved significantly (from 209 cells/mm3 to 324 cells/mm3). Comment: As pointed out by the authors, providing access to specialty HIV care and ART is not enough if we are to achieve desired levels of good overall health among HIV-infected patients with high rates of poverty and comorbidities. The effective expansion of services to address issues such as mental health, substance abuse, homelessness, and joblessness, as well as concurrent medical problems (e.g., HCV, smoking, and diabetes) is clearly necessary but remains a challenge in the current era of resource restrictions. Keith Henry, MD Published in Journal Watch HIV/AIDS Clinical Care July 18, 2011

CITATION(S):
Dowdy DW et al. Mortality among antiretroviral-eligible patients in an urban public clinic. J Acquir Immune Defic Syndr 2011 Aug 1; 57:297.

Diagnosing PCP with a Blood Test

Assessment of blood -glucan levels is a good, but not perfect, adjunctive test for HIV-related PCP. Pneumocystis jirovecii pneumonia (PCP) is usually diagnosed by direct visualization of the organism in respiratory secretions. Serum levels of (1 3)--D-glucan (-glucan), a component of many fungi, including P. jirovecii, have been found to be elevated in patients with PCP. To assess whether testing blood -glucan levels might be useful in diagnosing HIV-related PCP, investigators evaluated this assay in HIV-infected patients presenting with a wide variety of opportunistic infections (OIs).

Of 282 participants in ACTG 5164 (PLoS ONE 2009; 4:e5575 and2010; 5:e11416), 252 had an analyzable -glucan result. PCP was the most common qualifying OI, occurring in 69% of patients. Other common OIs were cryptococcal meningitis (14%) and bacterial pneumonia (9%). Using an 80 pg/mL threshold for positivity, 92% of patients with PCP had a positive -glucan result; of note, 35% of patients without PCP also had a positive result. Thus, the test sensitivity was 92%, and the specificity was 65%. In this study population, the positive predictive value of the test was 85%, and the negative predictive value was 80%. Some patients without PCP who had an elevated -glucan level turned out to be infected with other fungi, such as Histoplasma (which produces the marker) orCryptococcus (which may produce it at very low levels, although -glucan is not a reliable test for such infection). Comment: This study suggests that -glucan assessment is a useful adjunctive test when considering the diagnosis of PCP in HIV-infected patients. As with other tests, the clinician must interpret the result wisely. In a patient who is strongly suspected of having PCP but has a negative -glucan test, additional testing should be performed, including an induced sputum; if the latter is unrevealing, a bronchoalveolar lavage or empirical therapy should be considered. Conversely, in a patient who is notstrongly suspected of having PCP but has a positive -glucan test a not uncommon scenario I would look for an alternative diagnosis, such as an invasive fungal infection, or a cause of a false-positive -glucan result, such as hemodialysis or recent administration of particular antimicrobial agents or immunoglobulins. Although the blood -glucan test is not perfect, it is still good and, remember, perfect is the enemy of good! Rajesh T. Gandhi, MD The Editor-in-Chief of Journal Watch AIDS Clinical Care was involved in the research described here and was therefore not involved in the selection, writing, or review of this summary. Published in Journal Watch HIV/AIDS Clinical Care July 18, 2011

CITATION(S):
Sax PE et al. Blood (1 3)--D-glucan as a diagnostic test for HIV-related Pneumocystis

jirovecii pneumonia. Clin Infect Dis2011 Jul 15; 53:197. Original article (Subscription may be required) Medline abstract (Free)

Morris AM and Masur H. A serologic test to diagnose Pneumocystis pneumonia: Are we there yet? Clin Infect Dis 2011 Jul 15; 53:203.

A Potential Weak Spot on HIV

Mathematical analysis of HIV mutations identified a relatively conserved group of amino acids, within the Gag protein, that is critical for viral fitness and could be a vaccine target. HIV is able to cause persistent infection by generating mutations that allow the virus to elude both antibody and cytotoxic T-lymphocyte defenses. Mapping single amino-acid mutations in the HIV genome is one approach to understanding how mutations allow the virus to evade host immune response, but such an analysis does not take into account how mutations interact with one another to influence viral fitness. Investigators recently employed a mathematical technique, called random matrix theory (RMT), to address this issue. Using RMT to analyze a massive set of HIV sequences, the researchers identified a group of amino acids in the Gag polyprotein that rarely had more than one mutation occurring across it at a time. The researchers hypothesized that because this group (called Gag sector 3) rarely had multiple mutations, the involved amino acids must be critical to viral fitness and could, as a group, be a key target for immunological control of the virus. In support of their hypothesis, they found that 68% of the amino acids in the group influence the formation of the viral capsid and that the group as a whole is preferentially targeted by the immune systems of HIV elite controllers (individuals who can durably control HIV infection without medication). Comment: This work provides a powerful new approach to our understanding of the conserved regions of HIV that are essential for survival of the virus, thereby allowing a rational approach to the development of new vaccines. Richard T. Ellison III, MD Published in Journal Watch HIV/AIDS Clinical Care July 11, 2011

CITATION(S):
Dahirel V et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proc Natl Acad Sci U S A2011 Jun 20; [e-pub ahead of print]. (http://dx.doi.org/10.1073/pnas.1105315108)

TB Prophylaxis in HIV-Infected Adults: Stick with the WHO Recommendations

In an open-label clinical trial, taking isoniazid alone for 6 months was just as effective as taking it for longer or adding rifamycin. Isoniazid is effective in preventing tuberculosis (TB) and is currently recommended by the WHO (at a dose of 300 mg daily for 6 months) for all HIV-infected individuals who have a positive tuberculin skin test or are living in areas where skin testing is not feasible and the prevalence of latent TB exceeds 30%. Unfortunately, isoniazid prophylaxis is not widely used because of concerns about drug resistance, low adherence rates, and the potential for reinfection.

In this open-label, randomized trial, researchers evaluated the efficacy of three alternative TB prophylactic regimens relative to standard isoniazid therapy. A total of 1148 HIV-infected adults in South Africa who had a positive tuberculin skin test but were not yet on antiretroviral therapy were randomized to receive one of the following: Rifapentine (900 mg) plus isoniazid (900 mg) once weekly for 12 weeks Rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks Isoniazid (300 mg) daily for the duration of the study ( 6 years; continuous isoniazid) Isoniazid (300 mg) daily for 6 months (controls)

The overall incidence of TB was 1.9 cases per 100 person-years. The incidence of TB or death (a composite endpoint) did not differ significantly between any of the alternative-regimen groups and the control group: 3.1 per 100 person-years in the rifapentineisoniazid group, 2.9 in the rifampinisoniazid group, 2.7 in the continuous isoniazid group, and 3.6 in the control isoniazid group. The continuous isoniazid group (which received the drug daily for a median of 3.3 years) had the highest rates of serious adverse events and of both temporary and permanent treatment discontinuation. Comment: These findings suggest that the alternative prophylactic treatments evaluated here achieve outcomes similar to those attained with the standard, WHO-recommended 6-month course of isoniazid treatment. No benefit is gained by taking isoniazid for more than 6 months or by adding rifampin or rifapentine. The current WHO-recommended regimen is as effective as (and cheaper than) longer isoniazid regimens or combination treatments. Salim S. Abdool Karim, MD, PhD Published in Journal Watch HIV/AIDS Clinical Care July 11, 2011

CITATION(S):
Martinson NA et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011 Jul 7; 365:11. Medline abstract (Free)

Current Approaches to Treating Kaposi Sarcoma

Here we present two case vignettes highlighting the clinical problem of Kaposi sarcoma. We then provide a primer on current treatment approaches. Case 1: A 26-year-old HIV-infected man with a history of poor adherence to antiretrovirals and a CD4 count of 30 cells/mm3presents with rectal bleeding, fever, and shortness of breath. He is found to have diffuse lymphadenopathy, pulmonary nodules, proctocolitis, a rectal mass, liver lesions,

thrombocytopenia, and hyperpigmented skin nodules. Endoscopy reveals nodular lesions in the esophagus and duodenum (see images), and pathologic reports from lymph-node and colon biopsies indicate Kaposi sarcoma (KS). Case 2: A 37-year-old HIV-infected man with a CD4 count of 13 cells/mm3 starts antiretroviral therapy (ART), as well as dapsone for Pneumocystis jirovecii pneumonia prophylaxis. Two weeks later, he presents with acute dyspnea and cyanosis and is found to have methemoglobinemia secondary to dapsone. He responds rapidly to treatment with methylene blue, but chest imaging incidentally reveals pulmonary nodules, and further work-up demonstrates mesenteric lymphadenopathy. He has multiple hyperpigmented nodular skin lesions and is diagnosed with presumed disseminated KS. How would you manage these two patients?

THE CLINICAL PROBLEM

KS has become rare in the developed world since the advent of potent ART. However, as illustrated by the above recent cases from U.S. clinics, this disease still occurs and can be life-threatening in patients with advanced HIV-related immunosuppression. Clinicians should therefore remain familiar with treatment options.

ETIOLOGY AND PRESENTATION

KS is an angioproliferative malignancy and remains the most common type of cancer among HIV-infected patients. It is caused by Kaposi sarcomaassociated herpesvirus, also known as human herpesvirus type 8 (HHV-8), which is the causative agent in primary effusion lymphoma and multicentric Castleman disease.1,2,3 Although multiple modes of transmission have been documented for this virus, saliva is likely the most common source of exposure. Progression from HHV-8 infection to clinical disease occurs when T-cell immunity is impaired, as in patients with suppressed CD4-cell counts. HIV infection amplifies HHV8 replication and increases the severity of disease. The clinical presentation of KS ranges from limited mucocutaneous disease, which most commonly occurs on the extremities and in the oropharynx, to widespread skin or visceral involvement. KS skin lesions vary in appearance but are typically brown or violaceous nodules, papules, or plaques. The most frequent visceral sites are the lungs, gastrointestinal tract, and lymph nodes.

DIAGNOSIS
KS is typically suggested by clinical appearance and can be confirmed by pathologic evaluation. Serologic tests for HHV-8 exist but are not readily available for clinical use, and utility is limited. Serum levels of HHV-8 DNA, quantified by polymerase chain reaction (PCR), have been correlated with the development of new KS lesions, but the role of this measure in diagnosis and management is debated.4 One study showed that HHV-8 PCR testing of pathologic specimens helped to differentiate cutaneous KS lesions from other lesions with similar appearance; however, such testing is not standard practice.5

TREATMENT AND MANAGEMENT STRATEGIES

Restoration of the immune system is key to treatment of HHV-8associated disease. Therefore, treatment of AIDS-associated KS should always involve ART. The choice of antiretroviral regimen for patients with KS is generally the same as that for other HIVinfected patients. Although initial reports in the literature described possible preferential benefit from protease inhibitors (PIs), based on inhibition of angiogenesis and tumor growth in vitro, more-recent studies have shown no difference between PI-containing and PI-sparing regimens with respect to KS regression or clinical outcomes.6 Regardless of the regimen used, clinicians should remember that KS symptoms, including both skin lesions and organ dysfunction from visceral disease, can flare shortly after ART initiation as a result of immune reconstitution inflammatory syndrome (IRIS). Most patients with limited cutaneous disease show tumor regression with ART alone. For those with large or nonresponsive skin lesions, referral to an experienced dermatologist is recommended, as the potential treatment options are vast. They include local radiation, topical alitretinoin, liquid nitrogen, electron beam or laser therapy, photodynamic therapy, intralesional chemotherapy (most often with vinblastine), intralesional interferon-, and intralesional human chorionic gonadotropin. CHEMOTHERAPY In cases of severe disease, ART is sometimes given together with chemotherapy. Three chemotherapeutic agents are approved by the FDA for advanced KS: pegylated liposomal doxorubicin, liposomal daunorubicin, and paclitaxel. Other agents such as bleomycin and etoposide also have activity but are more toxic. Pegylated liposomal doxorubicin is the most commonly used agent in the U.S. and is given intravenously at 20 mg/m2 every 3 weeks. This liposomal anthracycline is better tolerated than other agents and, when used alone, produces response rates in the range of 46% to 59%.7,8 When this agent is combined with ART, response rates are even higher (>70%) and exceed those seen with ART alone.9 However, a relapse rate of 13.5% per year has been reported with combination therapy.10Furthermore, a retrospective analysis of 64 patients with confirmed KS showed that although 77% had signs of improvement at 3 years, only 51% had complete resolution at that point.11 In that study, recent chemotherapy and combination ART were the only factors associated with improvement, and only combination ART was associated with resolution. Notably, the positive effects of ART did not vary with the class of medication used. Because chemotherapy carries risk and some patients will respond to ART alone, chemotherapy is not recommended for all patients. Clinicians must weigh the risks and benefits with each individual patient, preferably in consultation with an oncologist. Several indications for chemotherapy have been described, including advanced or rapid disease, poor response to ART, and end-organ dysfunction. The 2008 British HIV Association guidelines provide perhaps the most detailed list of potential indications. They include widespread skin involvement (>20 lesions), extensive oral cavity lesions, tumor-associated edema or ulceration, symptomatic visceral involvement, and IRIS-induced flare.12

ANTIHHV-8 AGENTS Antiviral medications with activity against HHV-8 have been proposed as another potential treatment modality for KS. Ganciclovir, foscarnet, and cidofovir all have activity against HHV-8 in vitro, and retrospective analyses have shown reduced KS risk among HIV-infected patients receiving these agents for other indications, such as cytomegalovirus retinitis. Clinical trial data, however, are limited. One study showed decreased HHV-8 replication with valganciclovir,13 but there is no trial demonstrating that these antiviral medications have clinical benefits for KS; a pilot study of cidofovir showed no benefit.14One theory for this lack of clinical response to antivirals is that few cells within KS lesions contain virus in the lytic phase of the life cycle, which is the phase at which antivirals are active (most KS cells contain virus in the latent phase). NOVEL THERAPIES Several novel therapies are also being investigated for the treatment of KS. These include drugs that target vascular endothelial growth factors, tyrosine kinase, matrix metalloproteinases, and a number of molecular signaling pathways. Conclusion The two patients described in the vignettes illustrate the complexity of managing KS in clinical practice today and demonstrate the need for case-by-case decision making with respect to chemotherapy. Patient 1 was stabilized in the hospital and restarted on ART; he began receiving pegylated liposomal doxorubicin every 3 weeks. After 5 months (6 cycles of chemotherapy), his skin lesions resolved, his CD4 count reached 84 cells/mm3, and computed tomography scans showed near-complete resolution of visceral disease and lymphadenopathy. Patient 2 was evaluated by the oncology team for presumed disseminated KS, but they decided against chemotherapy given the lack of clinical symptoms. Over the next 12 months, with ART alone, the patient's visceral disease resolved and his skin lesions improved dramatically. In summary, KS remains an important clinical entity that causes a wide spectrum of disease in HIVinfected patients. Improving immune status with ART is the most critical element of treatment, but providers should also be aware of other available treatment modalities. In the setting of severe local or widely disseminated disease, clinicians should obtain oncology evaluation for possible systemic chemotherapy. Brian R. Wood, MD, and Paul E. Sax, MD Dr. Wood is a Fellow in the Division of Infectious Diseases at Brigham and Women's Hospital in Boston. He reports no conflicts of interest. Published in Journal Watch HIV/AIDS Clinical Care June 13, 2011

CITATION(S):
1. Sullivan RJ et al. Targeted therapy for Kaposi sarcoma.BioDrugs 2009 Apr 1; 23:69. Medline abstract (Free)

2. Casper C. New approaches to the treatment of human herpesvirus 8associated disease. Rev Med Virol 2008 Sep/Oct; 18:321. Medline abstract (Free) 3. Sullivan RJ et al. Epidemiology, pathophysiology, and treatment of Kaposi sarcomaassociated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis 2008 Nov 1; 47:1209. Original article (Subscription may be required) Medline abstract (Free)

4. Nsubuga MM et al. Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions. Cancer Lett 2008 May 18; 263:182. Medline abstract (Free) 5. Nuovo M and Nuovo G. Utility of HHV8 RNA detection for differentiating Kaposi's sarcoma from its mimics. J Cutan Pathol2001 May; 28:248. Medline abstract (Free) 6. Martinez V et al. Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer 2006 Apr 10; 94:1000. Medline abstract (Free) 7. Northfelt DW et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol 1998 Jul 1; 16:2445. Medline abstract (Free) 8. Stewart S et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma: International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol1998 Feb 1; 16:683. Medline abstract (Free) 9. Martn-Carbonero L et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma. AIDS 2004 Aug 20; 18:1737. Medline abstract (Free) 10. Martn-Carbonero L et al. Long-term prognosis of HIV-infected patients with Kaposi sarcoma treated with pegylated liposomal doxorubicin. Clin Infect Dis 2008 Aug 1; 47:410. Original article (Subscription may be required) Medline abstract (Free)

11. Nguyen HQ et al. Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: Characterizing the predictors of clinical response. AIDS 2008 May 11; 22:937. Medline abstract (Free) 12. Bower M et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med 2008 Jul; 9:336. Medline abstract (Free) 13. Casper C et al. Valganciclovir for suppression of human herpesvirus8 replication: A randomized, double-blind, placebo-controlled trial. J Infect Dis 2008 Jul 1; 198:23. Original article (Subscription may be required) Medline abstract (Free)

14. Little RF et al. A pilot study of cidofovir in patients with Kaposi sarcoma. J Infect Dis 2003 Jan 1; 187:149. Original article (Subscription may be required) Medline abstract (Free)

HIV Superinfection A Rare Event?

No cases of HIV superinfection were detected in a longitudinal analysis of 15 treatment-naive patients with self-reported high-risk sexual behavior. HIV superinfection (in which a patient with established infection acquires a genetically different strain of the virus) has been documented but is considered quite rare. Some experts argue, though, that without repeat viral typing, many cases of superinfection may be missed, especially in patients with repeated unsafe sexual encounters. Researchers analyzed 907 env and 672 gag sequences in 124 serum samples collected from 15 treatment-naive men in Amsterdam during periods of self-reported sexual risk (unprotected anal intercourse with at least two male partners, or a report of syphilis or gonorrhea, in the preceding 6 months). No cases of superinfection were detected during a median 5.8 person-years of follow-up. Comment: Some studies have suggested that the risk for HIV superinfection is as high as the risk for initial infection, but such results might have been a consequence of recruitment bias or flawed mathematical modeling. Although investigators analyzed several sequences per serum sample in the present study, the technique used might not have been sensitive enough to detect small populations of minority strains, especially if those strains were less fit than the predominant one. Superinfection was not detected in this relatively small cohort of patients, but the results might be different if patients with other transmission risks or those at even greater risk were investigated in a similar fashion. Helmut Albrecht, MD

Published in Journal Watch HIV/AIDS Clinical Care June 13, 2011

CITATION(S):
Rachinger A et al. Low incidence of HIV-1 superinfection even after episodes of unsafe sexual behavior of homosexual men in the Amsterdam Cohort Studies on HIV Infection and AIDS. J Infect Dis 2011 Jun 1; 203:1621.