AIDS-defining Conditions Research Articles

Chronic Hepatitis B and C Virus Infection and Risk for Non-Hodgkin Lymphoma in HIV-Infected Patients: A Cohort Study.

Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIV-infected patients. Cohort study. 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. A total of 52479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. In HIV-infected patients receiving ART, chronic co-infection with HBV and HCV is associated with an increased risk for NHL. European Union Seventh Framework Programme.

Review of cytomegalovirus coinfection in HIV-infected individuals in Africa

Cytomegalovirus (CMV) infection among HIV-infected individuals may cause end-organ disease, which is an AIDS-defining condition. Evidence from high-income countries suggests that CMV may alter the outcome of HIV infection, other than causing end-organ diseases. We reviewed literature on HIV and CMV coinfection in Africa. Systematic review of published studies on HIV and CMV coinfection in Africa using the PubMed database. High CMV seroprevalence was found throughout Africa, exceeding 90% in most populations. Retinitis, pneumonia, and colitis were the most commonly reported CMV manifestations in HIV-infected individuals. Among patients with pulmonary symptoms, the prevalence of CMV pneumonitis varied from 20% to over 60%, whereas CMV was found in 0% to 14% of patients with gastrointestinal manifestations. Cytomegalovirus retinitis was found in 0% to 2.6% of examined HIV-infected individuals. The diagnostics of CMV end-organ diseases were found complex and difficult to interpret in African settings. Cytomegalovirus viremia was correlated with significantly lower CD4 cell count and increase in activated and apoptosis vulnerable T-lymphocytes. Also, CMV coinfection was found to be associated with increased transmission and progression of HIV infection. Moreover, detectable CMV DNA was an independent predictor of HIV transmission and mortality among HIV-infected individuals. Cytomegalovirus is highly prevalent in Africa and a common cause of disease manifestations in HIV-infected individuals among all age groups. Cytomegalovirus coinfection in HIV-infected individuals in Africa is associated with increased transmission and mortality of HIV, but it is a neglected area of research.

Evaluation of HIV testing recommendations in specialty guidelines for the management of HIV indicator conditions.

ObjectivesEuropean guidelines recommend HIV testing for individuals presenting with indicator conditions (ICs) including AIDS‐defining conditions (ADCs). The extent to which non‐HIV specialty guidelines recommend HIV testing in ICs and ADCs is unknown. Our aim was to pilot a methodology in the UK to review specialty guidelines and ascertain if HIV was discussed and testing recommended.Methods UK and European HIV testing guidelines were reviewed to produce a list of 25 ADCs and 49 ICs. UK guidelines for these conditions were identified from searches of the websites of specialist societies, the National Institute of Clinical Excellence (NICE) website, the NICE Clinical Knowledge Summaries (CKS) website, the Scottish Intercollegiate Guidance Network (SIGN) website and the British Medical Journal Best Practice database and from Google searches.ResultsWe identified guidelines for 12 of 25 ADCs (48%) and 36 of 49 (73%) ICs. In total, 78 guidelines were reviewed (range 0–13 per condition). HIV testing was recommended in six of 17 ADC guidelines (35%) and 24 of 61 IC guidelines (39%). At least one guideline recommended HIV testing for six of 25 ADCs (24%) and 16 of 49 ICs (33%). There was no association between recommendation to test and publication year (P = 0.62).ConclusionsThe majority of guidelines for ICs do not recommend testing. Clinicians managing ICs may be unaware of recommendations produced by HIV societies or the prevalence of undiagnosed HIV infection among these patients. We are piloting methods to engage with guideline development groups to ensure that patients diagnosed with ICs/ADCs are tested for HIV. We then plan to apply our methodology in other European settings as part of the Optimising Testing and Linkage to Care for HIV across Europe (OptTEST) project.

The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis.

The aim of the study was to describe the characteristics of HIV-infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. Indicator conditions are still missed by clinicians. Women and 'non-MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection.

Impact of public health strategies on reducing AIDS mortality in southern Brazil

In Brazil, all patients who fulfill the criteria for AIDS have had free access to antiretroviral therapy since 1996. We performed this cross-sectional study to evaluate the causes of death among 643 HIV-infected patients over three non-consecutive years (2000, 2006, and 2010), using their epidemiological, clinical, and laboratory data. The causes of death were classified as AIDS-defining or non-AIDS-defining conditions. We observed a progressive increase in the prevalence of HIV infection over the study period, although there was also a decrease in the mortality rate for various groups, and especially among pediatric patients. An AIDS-defining condition was recorded as the cause of death for approximately 30% of the patients. There was also a high frequency (>70%) of infectious and parasitic diseases, including opportunistic infections, and the most common diagnoses were septicemia, pneumonia, tuberculosis, and pneumocystosis. Acute respiratory failure was the underlying cause of death in 30% of these cases. Despite advances in HIV therapy, the mortality rate remains high in Brazil. As few Brazilian studies have investigated HIV/AIDS-related mortality, it is important to evaluate and improve the mortality notification databases, in order to provide information regarding the effects of HIV and to guide the implementation of appropriate healthcare measures.

Effect of BMI and fat mass on HIV disease progression in HIV-infected, antiretroviral treatment-naïve adults in Botswana.

An obesity paradox has been proposed in many conditions including HIV. Studies conducted to investigate obesity and its effect on HIV disease progression have been inconclusive and are lacking for African settings. This study investigated the relationship between overweight/obesity (BMI≥25 kg/m2) and HIV disease progression in HIV+ asymptomatic adults not on antiretroviral treatment (ART) in Botswana over 18 months. A cohort study in asymptomatic, ART-naïve, HIV+ adults included 217 participants, 139 with BMI of 18·0-24·9 kg/m2 and seventy-eight participants with BMI≥25 kg/m2. The primary outcome was time to event (≥25 % decrease in cluster of differentiation 4 (CD4) cell count) during 18 months of follow-up; secondary outcomes were time to event of CD4 cell count<250 cells/µl and AIDS-defining conditions. Proportional survival hazard models were used to compare hazard ratios (HR) on time to events of HIV disease progression over 18 months. Higher baseline BMI was associated with significantly lower risk of an AIDS-defining condition during the follow-up (HR 0·218; 95 % CI 0·068, 0·701; P=0·011). Higher fat mass at baseline was also significantly associated with decreased risk of AIDS-defining conditions during the follow-up (HR 0·855; 95 % CI 0·741, 0·987; P=0·033) and the combined outcome of having CD4 cell count≤250/µl and AIDS-defining conditions, whichever occurred earlier (HR 0·918; 95 % CI 0·847, 0·994; P=0·036). All models were adjusted for covariates. Higher BMI and fat mass among the HIV-infected, ART-naïve participants were associated with slower disease progression. Mechanistic research is needed to evaluate the association between BMI, fat mass and HIV disease progression.

HIV-indicator-condition-driven HIV testing: clinically effective but still rarely implemented

In the UK, outcomes for people living with HIV are excellent. However, a quarter of those living with HIV do not know their status, and almost half are diagnosed late. Strategies to broaden HIV testing are needed. HIV indicator conditions are those thought to be associated with HIV infection because they share risk factors (eg viral hepatitis) or because they arise as a result of early or late immunodeficiency (eg bacterial pneumonia, Kaposi's sarcoma). They comprise all AIDS-defining conditions, but also many non-AIDS-defining conditions spanning the spectrum of medicine. Patients presenting with indicator conditions should routinely be offered an HIV test. This approach is likely to be clinically effective, because knowledge of HIV status is essential in the management of many conditions. It is cost effective if the prevalence of HIV infection is greater than 0.1%. The strategy removes the need for risk assessment, and is acceptable to patients and healthcare practitioners. If broadly implemented, it is likely to be effective at a public health level, and will help to reduce both undiagnosed HIV and late diagnoses of HIV. Here we review the emerging evidence base that supports the value of routine HIV testing in indicator conditions.

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

Diagnosis of HIV-Associated Oral Lesions in Relation to Early versus Delayed Antiretroviral Therapy: Results from the CIPRA HT001 Trial.

Oral mucosal lesions that are associated with HIV infection can play an important role in guiding the decision to initiate antiretroviral therapy (ART). The incidence of these lesions relative to the timing of ART initiation has not been well characterized. A randomized controlled clinical trial was conducted at the GHESKIO Center in Port-au-Prince, Haiti between 2004 and 2009. 816 HIV-infected ART-naïve participants with CD4 T cell counts between 200 and 350 cells/mm3 were randomized to either immediate ART initiation (early group; N = 408), or initiation when CD4 T cell count was less than or equal 200 cells/mm3 or with the development of an AIDS-defining condition (delayed group; N = 408). Every 3 months, all participants underwent an oral examination. The incidence of oral lesions was 4.10 in the early group and 17.85 in the delayed group (p-value <0.01). In comparison to the early group, there was a significantly higher incidence of candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex in the delayed group. The incidence of oral warts in delayed group was 0.97 before therapy and 4.27 post-ART initiation (p-value <0.01). In the delayed group the incidence of oral warts post-ART initiation was significantly higher than that seen in the early group (4.27 versus 1.09; p-value <0.01). The incidence of oral warts increased after ART was initiated, and relative to the early group there was a four-fold increase in oral warts if ART was initiated following an AIDS diagnosis. Based upon our findings, candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex indicate immune suppression and the need to start ART. In contrast, oral warts are a sign of immune reconstitution following ART initiation.

The association between combination antiretroviral adherence and AIDS-defining conditions at HIV diagnosis

ABSTRACTCombination antiretroviral therapy (cART) has changed the clinical course of HIV. AIDS-defining conditions (ADC) are suggestive of severe or advanced disease and are a leading cause of HIV-related hospitalizations and death among people living with HIV/AIDS (PLWHA) in the USA. Optimal adherence to cART can mitigate the impact of ADC and disease severity on the health and survivability of PLWHA. The objective of this study was to evaluate the association between ADC at HIV diagnosis and optimal adherence among PLWHA. Using data from the 2008 and 2009 Medicaid data from 29 states, we identified individuals, between 18 and 49 years, recently infected with HIV and with a cART prescription. Frequencies and descriptive statistics were conducted to characterize sample. Univariate and multivariable Poisson regression analyses were employed to evaluate the association optimal cART adherence (defined as ≥ 95% study days covered by cART) and ADC at HIV diagnosis (≥1 ADC) were assessed. Approximately 17% of respondents with ADC at HIV diagnosis reported optimal cART adherence. After adjusting for covariates, respondents with an ADC at HIV diagnosis were less likely to report optimal cART adherence (adjusted prevalence ratio (APR) = 0.64, 95% confidence intervals (CI), 0.54–0.75). Among the covariates, males (APR=1.10, 95% CI, 1.02–1.19) compared to females were significantly more likely to report optimal adherence while younger respondents, 18–29 years (APR=0.67, 95% CI, 0.57–0.77), 30–39 years (APR=0.86, 95% CI, 0.79–0.95) compared to older respondents were significantly less likely to report optimal adherence. PLWHA with ADC at HIV diagnosis are at risk of suboptimal cART adherence. Multiple adherence strategies that include healthcare providers, case managers, and peer navigators should be utilized to improve cART adherence and optimize health outcomes among PLWHA with ADC at HIV diagnosis. Targeted adherence programs and services are required to address suboptimal adherence in this population.

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial.

BackgroundHIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.MethodsDouble-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.ResultsNo significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.ConclusionsThis study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.Trial RegistrationClinicalTrials.gov NCT01299948

Opportunistic Neurologic Infections in Patients with Acquired Immunodeficiency Syndrome (AIDS).

Infections of the central nervous system (CNS) in individuals with human immunodeficiency virus (HIV) remain a substantial cause of morbidity and mortality despite the introduction of highly active antiretroviral therapy (HAART) especially in the resource-limited regions of the world. Diagnosis of these infections may be challenging because findings on cerebrospinal fluid (CSF) analysis and brain imaging are nonspecific. While brain biopsy provides a definitive diagnosis, it is an invasive procedure associated with a relatively low mortality rate, thus less invasive modalities have been studied in recent years. Diagnosis, therefore, can be established based on a combination of a compatible clinical syndrome, radiologic and CSF findings, and understanding of the role of HIV in these infections. The most common CNS opportunistic infections are AIDS-defining conditions; thus, treatment of these infections in combination with HAART has greatly improved survival.

Feasibility of Interim PET-Adapted Therapy in HIV-Positive Patients with Advanced Hodgkin Lymphoma (HL): Sub-Analysis of SWOG S0816 Phase 2 Trial

Background: The risk of HL is 10-fold higher in HIV-infected individuals than in the background population. Patients with HIV-HL typically present with advanced stage disease and frequent extranodal sites of involvement, accounting for higher risk scores than HIV-negative counterparts. Despite that, the prognosis of HIV-HL in the HAART era has been favorable. Standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) results in complete response rates (74%) and five-year overall survival (80%) similar to those in non-HIV-HL. Thus, as in HIV-negative HL, exploration of response-adapted therapy in HIV-HL is well-justified. PET imaging after 2 cycles of chemotherapy was found to be a strong predictor of treatment outcome in patients with non-HIV-HL. Here, for the first time, we report on the outcomes of HIV-positive patients enrolled on S0816, a multicenter Phase 2 trial of response-adapted therapy of stage III-IV HL using interim FDG-PET imaging.Methods: HIV-positive patients aged 18-60 with previously untreated stage III-IV classical HL were eligible. Patients with multi-drug resistant HIV or concurrent AIDS-defining conditions were excluded. All patients received 2 cycles of ABVD followed by an interim PET, reviewed centrally. Patients with negative PET (Deauville≤3) subsequently received 4 additional cycles of ABVD, while PET-positive patients received 6 cycles of BEACOPP standard regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone).Results: 12 patients with HIV-HL received study treatment. Median age was 44.6 years (range, 25 to 50 years), 83.3% were male. 11/12 (91.6%) patients presented with bulky lymphadenopathy (≥10 cm) and 50% had poor risk international prognostic score (IPS≥4). 6/12 (50%) patients manifested B-symptoms and 33.3% had bone marrow involvement by HL. Where information was available, most patients (7/9, 77.8%) received concurrent HAART during chemotherapy. Median CD4 count prior to registration was 165/µL (range, 22-400/µL), and <100/µL in 5/12 pts (41.7%).All HIV-HL patients successfully completed 2 initial cycles of ABVD. Gr 4 neutropenia and gr 3 febrile neutropenia were common during this treatment (66% and 25%, respectively). 10/12 (83.3%) patients achieved PET-negative status and 2 remained PET-positive with Deauville scores of 4 and 5. All PET-negative patients continued therapy with ABVD. Of those, nine completed the 4 cycles of treatment and one discontinued early for progressive disease 4 months after registration on study. Of the PET-positive patients, one elected to receive ABVD therapy off the study protocol, while the other completed 6 cycles of BEACOPP; both achieved a partial response. Thus, following ABVD therapy, 82% of patients achieved complete response and 18% - partial response. With median follow-up of 31 months (range, 5.4-38.1 months) all study patients are alive. Two patients developed progressive disease, with the estimated progression-free survival of 83% at 2 years (95% CI, 46.1 to 95.3%). Most grade 3-4 adverse events with continued therapy were neutropenia (72.7%) and febrile neutropenia (27.2%), while other toxicities were uncommon (see Table). All 12 patients experienced at least one grade 3-4 toxicity during study treatment. 3 patients (25%) required dose reductions due to febrile neutropenia (N=2) and neuropathy (N=1).Conclusions. ABVD is highly effective in patients with advanced stage poor-risk HIV-HL and induces PET-negative responses at a similar rate without undue added toxicity as compared to non-HIV patients in a prospective trial setting. As response-adapted therapy evolves to be a standard approach for HIV-negative patients with advanced stage HL, the results of S0816 study presented here support a similar investigative approach in patients with HIV-HL, with the goal of reducing long-term toxicity. The role of intensified chemotherapy regimens in patients with HIV-HL who do not achieve PET-negative status needs further study. Table 1ToxicityGrade 3, N (%)Grade 4, N (%)Anemia2 (18.2)2 (18.2)Febrile neutropenia3 (27.2)-Lymphopenia1 (9.1)2 (18.2)Neutropenia2 (18.2)6 (54.5)Thrombocytopenia1 (9.1)-Infection2 (18.2)-Anorexia1 (9.1)-Dizziness1 (9.1)-Fatigue1 (9.1)-Hypophosphatemia1 (9.1)-Musculoskeletal pain1 (9.1)-Thrombosis1 (9.1)- DisclosuresSmith:Pharmacyclics: Consultancy; Celgene: Consultancy.

Brief Report: Consequences of Presentation With Advanced HIV Disease in Pregnancy: Data From a National Study in Italy.

Among 469 women with a diagnosis of HIV in pregnancy, 74 (15.8%) presented with less than 200 CD4 cells per cubic millimeter. The only variable significantly associated with this occurrence was African origin (odds ratio: 2.22, 95% confidence intervals: 1.32 to 3.75, P = 0.003). Four women with low CD4 (5.6%), compared with none with higher CD4 counts, had severe AIDS-defining conditions (P < 0.001) during pregnancy or soon after delivery, and one transmitted HIV to the newborn. Early preterm delivery (<32 weeks) was significantly more frequent with low CD4 (6.2% vs. 1.4%, P = 0.015). An earlier access to HIV testing, particularly among immigrants of African origin, can prevent severe HIV-related morbidity.

Auditing HIV Testing Rates across Europe: Results from the HIDES 2 Study.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32–97), lowest in Northern Europe (median 44%, IQR 22–68%) and highest in Eastern Europe (median 99%, IQR 86–100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0–4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Antiretroviral Therapy for Nevirapine-Exposed Children With HIV Infection.

Early in theHIVepidemic,patientswithAIDSwerenotalways diagnosed as having the disease, in some cases because their opportunistic infections (eg, disseminated histoplasmosis) were not yet recognized as AIDS-defining conditions. Sincethen,therehavebeenremarkableadvances inboththediagnosticcapabilitiesandtherapeuticoptions inthetreatmentofHIVdisease.Thisprogresshas resulted in restorationof severely ill patients’ immune systems and previously lethal HIV infection becoming a chronic disease. There has seldom been such successful and rapid progress for adiseasewithhighmorbidity and short life expectancy (eg, in the 1980s,>40%ofperinatally infectedchildrendiedbefore 4 years of age, whereas today, with optimal care, <1% die before 4 years of age1). However, the epidemic is not over, too manypeople avoid testing and too fewengage in care, andprophylaxis and treatment budgets are limited. The success of 3 ormore antiretroviral drugs (combination antiretroviral therapy [ART]) that decrease the viral capability to select multiple mutations necessary to confer resistance to 3-drugregimenshas resulted in lifelongsuppressionofHIVreplication in adherent patients. However, the outcome is less favorable in nonadherent patients, who often experience treatment failure and development of drug resistance.2 The use of combinationARTcanalso leadtomultipleadverseevents, some that are serious (eg, liver failure, cardiovascular disease), and some that cause significant morbidity (eg, diarrhea, anemia). Severalstudiessuggestedthatreductioninpillburdenandoncedailydosingincreasedadherence.3,4Althoughthesestudiesmay have been biased by comparing different drugs (eg, twicedaily lopinavir vs once-daily efavirenz) that may have different tolerability, toxicity, or both, the general consensus is that single daily dosing improves adherence.5 Inapreviousstudy,Coovadiaetal6 evaluatedwhetherchildren initially treated with ritonavir-boosted lopinavir–based therapy could be safely switched to nevirapine-based therapy soon after achieving viral load suppression and found that resistance tonevirapine selectedduringexposure to thisdrug for preventionofmother-to-child transmission led toahigher rate of virologic failure in childrenwho transitioned to nevirapine. In this issueof JAMA, Coovadia andcolleagues7 report ona randomized, open-label noninferiority trial in Johannesburg, South Africa, to evaluate whether nevirapine-exposed children who achieved initial viral suppression while receiving ritonavir-boosted lopinavir could transition to efavirenz without risk of viral failure. The authors enrolled 298 HIV-infected children aged 3 years or older (mean age, 4.3 years) exposed to nevirapine forpreventionofmother-to-child transmissionwho hadplasmaHIVRNAlevelsof less than50copies/mLwhile taking ritonavir-boosted lopinavir. Patients were randomized to switch to efavirenz (n = 150) or to continue taking ritonavirboosted lopinavir (n = 148) andwere followed up for 48weeks after randomization. The probability of viral rebound by 48 weeks was 17.6% (n = 26) in the efavirenz group and 28.4% (n = 42) in the ritonavir-boosted lopinavir group, and theprobabilitiesofviral failurewere2.7%(n = 4)withefavirenzand2.0% (n = 3) with ritonavir-boosted lopinavir. The authors conclude thatswitchingtoefavirenzvscontinuingritonavir-boosted lopinavir did not result in significantly higher rates of viral rebound or viral failure. The finding that transition to efavirenz-based therapywas better than previously observedwith transition to nevirapinebased therapy shouldnot be surprising, as several studies have previously described superior virologic and immunologic outcomeswithefavirenzvsnevirapine.8-10However, inmanycountries,nevirapineisstillcommonlyused,andsubstantialtreatment failureanddeathcontinuetooccurbecauseof the increasedrate ofvirologicfailurewithnevirapinecomparedwithefavirenz.The recentWorldHealthOrganization (WHO)guidelinescontinueto strongly recommend a nevirapine-based regimen as first-line combinationART for childrenyounger than3years if ritonavirboostedlopinavir–basedtherapyisnotfeasible.11 It ispossiblethat combinationsthat includenevirapinemaybepreferredbymany countriesbecauseoflowercost.Thisapproachmayleadtohigher failure rates,which in the long runmaybemore costly because of the increasedneed formore expensive second-line therapy. EventhoughCoovadiaetalsuggestthattheirstudy“provides evidence to support the safety and efficacy of switching to efavirenz,”7 severalquestions remain.ThecurrentWHOdosing recommendationforefavirenzmayresult inahigherproportion of children with excessive blood levels, which may lead to increased toxicity.12 Is it possible that thehighpercentageof childrenwithnightmaresandsleepingproblemsinthecurrentstudy (1 in4children)representssuchtoxicity?Howmanyofthesechildrenalsohadimpairedconcentrationandother, lessobviouscentralnervoussystemtoxiceffects?Althoughtheseadverseevents aremorecommoninthefirstfewweeksafterefavirenztreatment is started,an importantconsideration ishowmanypatientswill not adhere to the regimen during those weeks, increasing the chance for resistance to develop. Thepossible role of other factors affecting thepharmacokinetics andpharmacodynamics of efavirenz, such as nutritional status and developmental physiology(especially in those<3yearsofage, forwhomthedrugwas recently approved by the US Food and Drug Administration), Related article page 1808 Opinion

Polyketides, toxins and pigments in Penicillium marneffei.

Penicillium marneffei (synonym: Talaromyces marneffei) is the most important pathogenic thermally dimorphic fungus in China and Southeastern Asia. The HIV/AIDS pandemic, particularly in China and other Southeast Asian countries, has led to the emergence of P. marneffei infection as an important AIDS-defining condition. Recently, we published the genome sequence of P. marneffei. In the P. marneffei genome, 23 polyketide synthase genes and two polyketide synthase-non-ribosomal peptide synthase hybrid genes were identified. This number is much higher than those of Coccidioides immitis and Histoplasma capsulatum, important pathogenic thermally dimorphic fungi in the Western world. Phylogenetically, these polyketide synthase genes were distributed evenly with their counterparts found in Aspergillus species and other fungi, suggesting that polyketide synthases in P. marneffei did not diverge from lineage-specific gene duplication through a recent expansion. Gene knockdown experiments and ultra-high performance liquid chromatography-photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry analysis confirmed that at least four of the polyketide synthase genes were involved in the biosynthesis of various pigments in P. marneffei, including melanin, mitorubrinic acid, mitorubrinol, monascorubrin, rubropunctatin, citrinin and ankaflavin, some of which were mycotoxins and virulence factors of the fungus.

HIV control in postpartum mothers: a turbulent time

We conducted an audit looking at the management of HIV-positive women in the postpartum period. We found that of the women with a previous AIDS-defining condition or a CD4 count <350 cells/µL, 83% were correctly continued on antiretroviral therapy (ART) and 84.1% of these had good virological control. ART was correctly stopped in 100% of women who had always had a CD4 count >500 cells/µL. A significant finding from our audit was that all of the women who had poor virological control or stopped ART against medical advice had social issues or self-reported depression. The main recommendation was to extend the pregnancy multidisciplinary team (MDT) meeting to include the 12-month postpartum period to offer support to women to try to improve treatment outcomes.

Using the pathogenic and nonpathogenic nonhuman primate model for studying non-AIDS comorbidities.

With the advent of antiretroviral therapy that can control virus replication below the detection levels of conventional assays, a new clinical landscape of AIDS emerged, in which non-AIDS complications prevail over AIDS-defining conditions. These comorbidities are diverse and affect multiple organs, thus resulting in cardiovascular, kidney, neurocognitive and liver disease, osteopenia/osteoporosis, and cancers. A common feature of these conditions is that they are generally associated with accelerated aging. The mechanism behind these comorbidities is chronic excessive inflammation induced by HIV infection, which persists under antiretroviral therapy. Progressive simian immunodeficiency virus (SIV) infection of nonhuman primates (NHPs) closely reproduces these comorbidities and offers a simplified system in which most of the traditional human risk factors for comorbidities (i.e., smoking, hyperlipidemia) are absent. Additionally, experimental conditions can be properly controlled during a shorter course of disease for SIV infection. As such, NHPs can be employed to characterize new paradigms of AIDS pathogenesis and to test the efficacy of interventions aimed at alleviating non-AIDS-related comorbidities.

Healthcare costs associated with antiretroviral adherence among medicaid patients.

The relationship of antiretroviral therapy (ART) adherence to total healthcare expenditures for Medicaid-insured people living with HIV or AIDS (PLWHA) is not well understood, especially among asymptomatic HIV-positive patients. This study examined Medicaid-insured HIV-positive and AIDS-diagnosed patient groups to determine the association of ART adherence to mean monthly total healthcare expenditures in the 24-month measurement period, controlling for demographic, geographic, insurance, and clinical factors. The present study extends the existing literature by analyzing the relationship of ART adherence to total healthcare costs for asymptomatic HIV-positive patients separately from those patients with AIDS-defining conditions. This retrospective study utilized claims data from Florida Medicaid claims from July 2006 through June 2011. All patients (n=502) were HIV-positive, aged 18-64years, non-pregnant, and ART naïve for at least 12months prior to the measurement period. Each patient was categorized, based on medication possession ratios, as adherent (≥90%) or non-adherent (<90%), and were divided into two groups: HIV positive (n=232) and AIDS diagnosed (n=270). Generalized linear models predicted the mean monthly total expenditures for the non-adherence group versus the adherence group. For the HIV-positive group, the adjusted mean monthly expenditures for the non-adherent group were US$1,291; the adherent group adjusted mean monthly expenditures were US$1,926. The HIV-positive non-adherent group adjusted mean monthly expenditures were significantly less than the adherent group (-40%, p<0.001). However, for the AIDS-diagnosed group, there was not a statistically significant association of ART adherence to total healthcare expenditures (p=0.29). The results show that the relationship of ART adherence to healthcare costs is more complex than previously reported.