Willem Daniel Francois Venter

Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study

Objective:To determine the incidence, clinical manifestations, risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. Design:Prospective surveillance cohort and nested case–control study in a large, University hospital-based antiretroviral therapy (ART) clinic. Methods:A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case–control study with controls matched to IRIS cases on ART duration. Results:During the first 6 months of ART, 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44, 41%), abscess formation and suppurative folliculitis (8/44, 18.2%), varicella zoster (6/44, 13.6%), herpes simplex (4/44, 9.1%), cryptococcal meningitis (3/44, 6.8%), molluscum contagiosum (3/44, 6.8%), and Kaposis sarcoma (2/44, 4.5%). Median IRIS onset was 48 days (interquartile range, 29–99) from ART initiation. In comparison with controls, IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/μl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/μl; P = 0.05), but similar virological and immunological response to ART. In multivariable analyses, higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/μl increase). Most IRIS cases were mild, with ART discontinued in three (6.8%) patients, corticosteroids administered to four (9.1%) patients, and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. Conclusions:IRIS may affect 10% of patients initiating ART in Africa, particularly those with advanced immunosuppression, but severe, life-threatening IRIS is uncommon.

Immune reconstitution inflammatory syndrome (IRIS): Review of common infectious manifestations and treatment options

The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients initiating antiretroviral therapy (ART) results from restored immunity to specific infectious or non-infectious antigens. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden. The infectious pathogens most frequently implicated in the syndrome are mycobacteria, varicella zoster, herpesviruses, and cytomegalovirus (CMV). No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Prospective cohort studies addressing the optimal screening and treatment of opportunistic infections in patients eligible for ART are currently being conducted. These studies will provide evidence for the development of treatment guidelines in order to reduce the burden of IRIS. We review the available literature on the pathogenesis and epidemiology of IRIS, and present treatment options for the more common infectious manifestations of this diverse syndrome and for manifestations associated with a high morbidity.

Characteristics and outcomes of adult patients lost to follow-up at an antiretroviral treatment clinic in johannesburg, South Africa.

PURPOSE To report an 81-year-old woman with corneal neovascularization secondary to herpetic stromal keratitis treated with subconjunctival bevacizumab and to discuss the role of this novel antiangiogenic treatment. METHODS Case report and review of medical literature. RESULTS A dramatic regression of corneal vessels was observed 1 week after the injection. After a 3-month follow-up, there was no recurrence of corneal revascularization. CONCLUSIONS Bevacizumab may be a valid complementary treatment in patients with corneal neovascularization caused by herpetic stromal keratitis.Background:A significant proportion of those initiating antiretroviral treatment (ART) for HIV infection are lost to follow-up. Causes for discontinuing ART follow-up in resource-limited settings are not well understood. Methods:A retrospective analysis was conducted of all adult patients receiving ART at an urban public clinic in Johannesburg, South Africa between April 2004 and June 2005. Patients discontinuing follow-up for at least 6 weeks were identified and further studied, and causes for treatment default were tabulated. Results:Of 1631 adult patients studied, 267 (16.4%) discontinued follow-up during the study period. Gender, ethnicity, and age were not predictive of loss to follow-up. Of those discontinuing follow-up, 173 (64.8%) were successfully traced. Death accounted for 48% (n = 83) of those traced. Characteristics associated with death were older age at ART initiation (P = 0.022), lower baseline CD4 cell count (P = 0.0073), higher initial HIV RNA load (P = 0.024), and loss of weight on ART (P = 0.033). Date of death was known for 71% (n = 59) of patients traced deceased, of whom 83% (n = 49) had died within 30 days of active ART. Common nonmortality losses included relocation or clinic transfer (25.4%) and hospitalization or illness not resulting in death (10.4%). Few cited financial difficulty or medication toxicity as reasons for discontinuing follow-up. Conclusions:Nearly 1 in 6 patients receiving ART in a resource-constrained setting had discontinued follow-up over a 15-month period. Early mortality was high, especially in those with profound immunosuppression. Improving access to care and streamlining patient tracking may improve ART outcomes.

Providing immediate CD4 count results at HIV testing improves ART initiation.

BackgroundIn South Africa, CD4 count results are typically available within a week of testing. However, 35%–55% of newly diagnosed HIV-positive patients do not return for their CD4 results and therefore, do not access further care.12 We evaluated the impact of a CD4 count result and patient written information provided immediately after diagnosis on retention in care. MethodsHIV-infected subjects were randomized to 3 arms; receipt of a CD4 result at time of HIV diagnosis, receipt of written information, and standard of care (CD4 collection after 1 week) or standard of care alone. The outcome of interest was enrollment for further care within 1 month for pre-antiretroviral therapy (ART) care or within 3 months for ART initiation. Secondary outcome was time taken from diagnosis to each stage of care pathway. Independent predictors of retention were assessed with multivariate analysis. ResultsThree hundred forty-four patients recruited, of which 64.5% were females with a median age of 30 years (interquartile range: 27–35). Subjects were similar in age, gender, CD4 count, education, and employment status. Providing CD4 results at HIV diagnosis increases the likelihood of reporting for ART initiation (risk ratio = 2.1; 95% confidence interval = 1.39 to 3.17) compared with standard of care. Written information only reduced the time to presentation for pre-ART care although increasing age was associated with retention. There was 49% attrition in the standard of care arms. ConclusionsReceipt of a CD4 count at the time of HIV testing increases ART initiation rates. Point-of-care diagnostics can be used to improve retention, but losses to pre-ART care remain high.

Varied patterns of HIV-1 drug resistance on failing first-line antiretroviral therapy in South Africa.

Background:The South African national antiretroviral therapy roll-out program is entering its sixth year, with over 570,000 adults accessing treatment. HIV-1 drug resistance is a potential consequence of therapy. This study determined the pattern of HIV-1 drug resistance mutations after failure of first-line treatment regimens in South Africa. Methods:Two hundred and twenty-six patients virologically failing first-line regimens were studied to determine resistance patterns. Results:The most common reverse transcriptase mutation was M184V/I (72%; n = 163); 11% of patients (n = 25) had only nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations and 17% (n = 38) had no known resistance mutations. The K65R mutation was detected in 4%. The frequency of thymidine analog mutations was significantly higher with azidothymidine-containing (31 of 57) than stavudine-containing regimens (39 of 169; P < 0.001). The Y181C mutation was more frequent with failure of nevirapine (NVP)-containing (26%) than efavirenz (EFV)-containing therapy (3%; P < 0.001). The V106M mutation was more frequent with EFV (30%) than NVP (4%; P = 0.012). Conclusions:HIV-1 drug resistance patterns varied broadly after failure of first-line therapy, ranging from no known resistance mutations (17%) to multinucleoside reverse transcriptase inhibitor and NNRTI resistance (23%). NNRTI mutation profiles differed for patients on EFV- compared with NVP-containing regimens. Overall, these findings suggest that HIV-1 drug resistance testing would be useful in identifying most appropriate second-line regimens.

Causes of Death on Antiretroviral Therapy: A Post- Mortem Study from South Africa

Background Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. Methods HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. Results Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. Conclusions Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Emergence of X4 usage among HIV-1 subtype C: evidence for an evolving epidemic in South Africa.

This study investigated the genotype and phenotype of HIV-1 isolates of 20 South African AIDS patients. We found the highest percentage of CXCR4 usage among primary isolates, in which 30% efficiently utilized CXCR4 and exhibited the syncytium-inducing phenotype. Phylogenetic analysis of env confirmed that 19 of the 20 were subtype C, and syncytium-inducing viruses had genetic changes in the V3 loop, characteristic of CXCR4 usage. Results imply that the frequency of CXCR4-utilizing subtype C is increasing with time.

Protease Inhibitor Resistance Is Uncommon in HIV-1 Subtype C Infected Patients on Failing Second-Line Lopinavir/r-Containing Antiretroviral Therapy in South Africa

Limited data exist on HIV-1 drug resistance patterns in South Africa following second-line protease-inhibitor containing regimen failure. This study examined drug resistance patterns emerging in 75 HIV-1 infected adults experiencing virologic failure on a second-line regimen containing 2 NRTI and lopinavir/ritonavir. Ninety six percent of patients (n = 72) were infected with HIV-1 subtype C, two patients were infected with HIV-1 subtype D and one with HIV-1 subtype A1. Thirty nine percent (n = 29) of patients had no resistance mutations in protease or reverse transcriptase suggesting that medication non-adherence was a major factor contributing to failure. Major lopinavir resistance mutations were infrequent (5 of 75; 7%), indicating that drug resistance is not the main barrier to future viral suppression.

Evaluation of the Abbott m2000 RealTime Human Immunodeficiency Virus Type 1 (HIV-1) Assay for HIV Load Monitoring in South Africa Compared to the Roche Cobas AmpliPrep-Cobas Amplicor, Roche Cobas AmpliPrep-Cobas TaqMan HIV-1, and BioMerieux NucliSENS EasyQ HIV-1 Assays

ABSTRACT The implementation of antiretroviral therapy demands the need for increased access to viral load (VL) monitoring. Newer real-time VL testing technologies are faster and have larger dynamic ranges and fully automated extraction to benefit higher throughputs in resource-poor environments. The Abbott RealTime human immunodeficiency virus type 1 (HIV-1) assay was evaluated as a new option for testing for HIV-1 subtype C in South Africa, and its performance was compared to the performance of existing assays (the Cobas AmpliPrep-Cobas TaqMan HIV-1, version 1, assay; the AmpliPrep-Cobas Monitor standard HIV-1 assay; and the NucliSENS EasyQ-EasyMag HIV-1 assay) in a high-throughput laboratory. The total precision of the RealTime HIV-1 assay was acceptable over all viral load ranges. This assay compared most favorably with the Cobas AmpliPrep-Cobas TaqMan HIV-1 assay (R2 = 0.904), with a low standard deviation of difference being detected (0.323 copies/ml). The bias against comparator assays ranged from −0.001 copies/ml to −0.228 copies/ml. Variability in the reporting of VLs for a 20-member subtype panel compared to the variability of other assays was noted with subtypes G and CRF02-AG. The RealTime HIV-1 assay can test 93 samples per day with minimal manual preparation, less staff, and the minimization of contamination through automation. This assay is suitable for HIV-1 subtype C VL quantification in South Africa.

Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient

The protease inhibitor (PI) lopinavir–ritonavir (Kaletra) combination is a potent antiretroviral drug with a high resistance barrier. Primary failure as a result of PI resistance has not previously been described in an antiretroviral-naive patient. A 25-year-old black female South African patient was enrolled onto the Early Access Programme 6 November 2000. The patient had no history of international travel. Her baseline CD4 cell count was 282 cells/ml and her viral load was 325 000 copies/ml. (Roche Amplicor 1.5). She received 2 weeks of stavudine didanosine and hydroxyurea in June 2000 but the treatment was stopped after the patient developed eosinophilic folliculitis that was reported as a possible drug reaction by a dermatologist. She was given dual therapy because of the cost constraints at the time. (excerpt)