David J. Riedel

Clinical use of CCR5 inhibitors in HIV and beyond.

Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation.

Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection

Plasmablastic lymphoma of the oral cavity is a form of non-Hodgkin lymphoma (NHL) and was first described in 1997. We describe a case of plasmablastic lymphoma in an HIV-infected patient who presented with an expanding oral lesion and symptoms of a toothache. We review all cases of plasmablastic lymphoma that have been reported in the literature. Plasmablastic lymphoma is strongly associated with immunodeficiency, and most particularly, with HIV infection. The pathophysiological origin of plasmablastic lymphoma has not been fully characterised, but the presence of Epstein-Barr virus (EBV) has often been documented in biopsy specimens, supporting a role for EBV in the pathogenesis of this lymphoma. The differential diagnosis for an expanding oral lesion includes both infectious and malignant processes. Biopsy is essential for making a correct and prompt diagnosis. Treatment usually involves chemotherapy, but antiretroviral therapy may also have an important role. Infectious disease clinicians should be aware of this newly described and increasingly encountered lymphoma, since it is prominently associated with immunosuppression and may be mistaken for other entities.

Cell phone-based and internet-based monitoring and evaluation of the National Antiretroviral Treatment Program during rapid scale-up in Rwanda: TRACnet 2004-2010.

Background:Monitoring and evaluation of antiretroviral treatment (ART) scale-up has been challenging in resource-limited settings. We describe an innovative cell-phone-based and internet-based reporting system (TRACnet) utilized in Rwanda. Methods:From January 2004 to June 30, 2010, all health facilities with ART services submitted standardized monthly aggregate reports of key indicators. National cohort data were analyzed to examine trends in characteristics of patients initiating ART and cumulative cohort outcomes. Estimates of HIV-infected patients eligible for ART were obtained from Joint United Nations Program on HIV/AIDS (Estimation and Projection Package-Spectrum, 2010). Results:By June 30, 2010, 295 (65%) of 451 health centers, District and referral hospitals provided ART services; of these, 255 (86%) were located outside Kigali, the capital. Cell phone–based and internet-based reporting was used by 253 (86%) and 42 (14%), respectively. As of June 30, 2010, 83,041 patients were alive on ART, 6171 (6%) had died, and 9621 (10%) were lost-to-follow-up. Of those alive on ART, 7111 (8.6%) were children, 50,971 (61.4%) were female, and 1823 (2.2%) were on a second-line regimen. The proportion of all patients initiating ART at World Health Organization clinical stages 3 and 4 declined from 65% in 2005 to 27% in 2010. National ART coverage of eligible patients increased from 13% in 2005 to 79% in 2010. Conclusions:Rwanda has successfully expanded ART access and achieved high national ART coverage among eligible patients. TRACnet captured essential data about the ART program during rapid scale-up. Cell phone-based and internet-based reporting may be useful for monitoring and evaluation of similar public health initiatives in other resource-limited settings.

Natural viral suppressors of HIV-1 have a unique capacity to maintain γδ T cells

Objective:To evaluate Vγ2Vδ2 T cells in a group of HIV-infected patients who suppress HIV replication without antiretroviral therapy (natural viral suppressors, NVSs). Design:It is a cross-sectional study. Methods:We compared Vγ2Vδ2 T-cell frequency, T-cell repertoire, and responses to isopentenyl pyrophosphate stimulation between NVSs (n = 21) and HIV-uninfected controls (n = 27) and between NVSs and HIV-infected patients taking HAART with suppressed viral replication (HIV-P; n = 25). Results:NVSs had a mean frequency of 1.06 ± 0.82% CD3+Vδ2+ cells among total lymphocytes, which was significantly higher than both control groups (HIV-negative: 0.50 ± 0.53%, P = 0.042; HIV-P: 0.34 ± 0.37%, P = 0.002). The proportion of Vγ2 chains correlating with the Vγ2-Jγ1.2 rearrangement was reduced among NVSs compared with HIV-negative controls (0.57 ± 0.06 vs. 0.32 ± 0.04; P = 0.016) but was increased compared with HIV-P patients (0.32 ± 0.04 vs. 0.22 ± 0.03; P = 0.03). NVSs had a similar baseline frequency of CD27−/CD45RA− effector cells (19.6 ± 4.2%) compared with HIV-negative controls (20.8 ± 12.9%; P = 0.35). Conclusion:The altered γδ T-cell receptor repertoire among NVS was consistent with the known effect of HIV-1 on these cells. Uniquely among all HIV-infected groups, NVS reconstituted the γδ T-cell population, eventually reaching levels significantly above controls. This capacity to recover γδ T-cell numbers and function distinguishes individuals who control HIV-1 with and without HAART.

A Ten-Year Analysis of the Incidence and Risk Factors for Acute Pancreatitis Requiring Hospitalization in an Urban HIV Clinical Cohort

To assess the incidence of and risk factors for acute pancreatitis in HIV-infected patients in the contemporary highly active antiretroviral therapy (HAART) era, we evaluated all cases of acute pancreatitis requiring hospitalization between 1996 and 2006 in patients followed at Johns Hopkins Hospitals HIV clinic. A nested, case-control analysis was employed for initial episodes of acute pancreatitis, and conditional logistic regression was used to assess risk factors. Of 5970 patients followed for 23,460 person-years (PYs), there were 85 episodes of acute pancreatitis (incidence: 3.6 events/1000 PYs). The incidence of pancreatitis from 1996 to 2000 was 2.6 events/1000 PYs; the incidence from 2001 to 2006 was 5.1 events/1000 PYs (p = 0.0014, comparing rates in two time periods). In multivariate regression, factors associated with pancreatitis included female gender (adjusted odds ratio [AOR] 2.96 [1.69, 5.19]; p < 0.001); stavudine use (AOR 2.19 [1.16, 4.15]; p = 0.016); aerosolized pentamidine use (OR 6.27; [1.42, 27.63]; p = 0.015); and CD4 count less than 50 cells/mm(3) (AOR 10.47 [3.33, 32.90]; p < 0.001). Race/ethnicity, HIV risk factor, HIV-1 RNA, and newer non-nucleoside reverse transcriptase inhibitors (NNRTI)- and protease inhibitor (PI)-based HAART regimens were not associated with an increased risk of pancreatitis after adjustment for the above factors. Pancreatitis remains a significant cause of morbidity in the HIV population in the HAART era. Acute pancreatitis is associated with female gender, severe immunosuppression, and stavudine and aerosolized pentamidine usage. Of note, newer antiretrovirals, particularly atazanavir, lopinivir/ritonavir, tenofovir, abacavir, and efavirenz, were not associated with an increased risk of pancreatitis.

High cancer-related mortality in an urban, predominantly African-American, HIV-infected population.

Objective:To determine mortality associated with a new cancer diagnosis in an urban, predominantly African–American, HIV-infected population. Design:Retrospective cohort study. Methods:All HIV-infected patients diagnosed with cancer between 1 January 2000 and 30 June 2010 were reviewed. Mortality was examined using Kaplan–Meier estimates and Cox proportional hazards models. Results:There were 470 cases of cancer among 447 patients. Patients were predominantly African–American (85%) and male (79%). Non-AIDS-defining cancers (NADCs, 69%) were more common than AIDS-defining cancers (ADCs, 31%). Cumulative cancer incidence increased significantly over the study period. The majority (55.9%) was taking antiretroviral therapy (ART) at cancer diagnosis or started afterward (26.9%); 17.2% never received ART. Stage 3 or 4 cancer was diagnosed in 67%. There were 226 deaths during 1096 person years of follow-up, yielding an overall mortality rate of 206 per 1000 person years. The cumulative mortality rate at 30 days, 1 year, and 2 years was 6.5, 32.2, and 41.4%, respectively. Mortality was similar between patients on ART whether they started before or after the cancer diagnosis but was higher in patients who never received ART. In patients with a known cause of death, 68% were related to progression of the underlying cancer. Conclusion:In a large cohort of urban, predominantly African–American patients with HIV and cancer, many patients presented with late-stage cancer. There was substantial 30-day and 2-year mortality, although ART had a significant mortality benefit. Deaths were most often caused by progression of cancer and not from another HIV-related or AIDS-related event.

HIV drug resistance mutations among patients failing second-line antiretroviral therapy in Rwanda.

BACKGROUND Studies of patients failing second-line antiretroviral therapy (ART) in resource-limited settings (RLS) are few. Evidence suggests most patients who appear to be virologically failing do so not due to drug resistance but to poor adherence, which, if properly addressed, could allow continued use of less expensive first- and second-line regimens. Drug resistant mutations (DRMs) were characterized among patients virologically failing second-line ART in Rwanda. METHODS A total of 128 adult patients receiving second-line ART for at least 6 months were invited to participate; 74 agreed and had HIV-1 viral load (VL) measured. Resistance genotypes were conducted in patients with virological failure (VF; that is, VL ≥1,000 copies/ml). RESULTS In total, 35 patients met the criteria for VF. The median time on lopinavir/ritonavir-based second-line ART was 2.7 years. Of 30 successful resistance genotype analyses, 13 (43%) had ≥1 nucleoside reverse transcriptase inhibitor (NRTI) mutation, 18 (60%) had at least 1 non-NRTI mutation and 5 (17%) had at least 1 major protease inhibitor mutation. Eleven (37%) had virus without significant mutations that would be fully sensitive to first-line ART; 12 (40%) had DRM to first-line ART but sensitive to second-line ART. Only 7 patients (23%) demonstrated a DRM profile requiring third-line ART. CONCLUSIONS Among 30 genotyped samples of patients with VF on second-line ART, more than one-third had no significant DRMs, implicating poor adherence as the primary cause of VF. The majority of patients (77%) would not have required third-line ART. These findings reinforce the need for intensive adherence assessment and counselling for patients who appear to be failing second-line ART in RLS.

Estimation of the size of the female sex worker population in Rwanda using three different methods

HIV prevalence is disproportionately high among female sex workers compared to the general population. Many African countries lack useful data on the size of female sex worker populations to inform national HIV programmes. A female sex worker size estimation exercise using three different venue-based methodologies was conducted among female sex workers in all provinces of Rwanda in August 2010. The female sex worker national population size was estimated using capture–recapture and enumeration methods, and the multiplier method was used to estimate the size of the female sex worker population in Kigali. A structured questionnaire was also used to supplement the data. The estimated number of female sex workers by the capture–recapture method was 3205 (95% confidence interval: 2998–3412). The female sex worker size was estimated at 3348 using the enumeration method. In Kigali, the female sex worker size was estimated at 2253 (95% confidence interval: 1916–2524) using the multiplier method. Nearly 80% of all female sex workers in Rwanda were found to be based in the capital, Kigali. This study provided a first-time estimate of the female sex worker population size in Rwanda using capture–recapture, enumeration, and multiplier methods. The capture–recapture and enumeration methods provided similar estimates of female sex worker in Rwanda. Combination of such size estimation methods is feasible and productive in low-resource settings and should be considered vital to inform national HIV programmes.

The role of viral co-infection in HIV-associated non-AIDS-related cancers.

HIV-infected individuals are at increased risk for most types of cancer, including those typically classified as non-AIDS-defining cancers (NADCs). This increased risk is likely multifactorial, but a prominent risk factor for the increased rate of some cancers is co-infection with oncogenic viruses. Anal cancer, hepatocellular carcinoma, and Hodgkin lymphoma are three of the most common NADCs, and they are associated with co-infection with human papillomavirus, hepatitis B and C, and Epstein Barr virus, respectively. This review will examine the epidemiology, pathogenesis, and future trends around these virally associated NADCs frequently found in HIV-infected individuals.

HIV-associated lymphoma sub-type distribution, immunophenotypes and survival in an urban clinic population

HIV-infected patients have an increased risk for both Hodgkin and non-Hodgkin lymphomas. A retrospective cohort of all HIV-infected patients diagnosed with lymphoma in urban clinics from 2000–2013 was evaluated to characterize the distribution and determine effects of sub-type and immunophenotype on survival. Of 160 cases identified, 131 (82%) had complete information and were analyzed. The most common sub-types were diffuse large B cell (41%), Burkitt (21%) and Hodgkin lymphoma (18%). Advanced (78% stage III/IV) and extranodal disease (82%) at presentation were common. CD20 was the most commonly expressed immunophenotypic marker (89%). Overall mortality rate was high (26.1 per 100 person-years). Lower mortality was noted in CD10 + and CD20 + lymphomas, but differences were not statistically significant. After adjustment, low CD4 count (≤ 200) at diagnosis was associated with higher mortality (adjusted hazard ration (AHR) = 1.75; 95% CI = 1.00–3.61). Mortality in this cohort of patients with HIV-associated lymphomas was high and exceeds that from published data from the general population.