Michele Zeier

Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting

Background:In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure. Methods:We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study. Results:Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 μg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair. Conclusions:Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.

Treatment simplification in HIV-infected adults as a strategy to prevent toxicity, improve adherence, quality of life and decrease healthcare costs

Since the advent of highly active antiretroviral therapy (HAART), the treatment of human immunodeficiency virus (HIV) infection has become more potent and better tolerated. While the current treatment regimens still have limitations, they are more effective, more convenient, and less toxic than regimens used in the early HAART era, and new agents, formulations and strategies continue to be developed. Simplification of therapy is an option for many patients currently being treated with antiretroviral therapy (ART). The main goals are to reduce pill burden, improve quality of life and enhance medication adherence, while minimizing short- and long-term toxicities, reducing the risk of virologic failure and maximizing cost-effectiveness. ART simplification strategies that are currently used or are under study include the use of once-daily regimens, less toxic drugs, fixed-dose coformulations and induction-maintenance approaches. Improved adherence and persistence have been observed with the adoption of some of these strategies. The role of regimen simplification has implications not only for individual patients, but also for health care policy. With increased interest in ART regimen simplification, it is critical to study not only implications for individual tolerability, toxicity, adherence, persistence and virologic efficacy, but also cost, scalability, and potential for dissemination and implementation, such that limited human and financial resources are optimally allocated for maximal efficiency, coverage and sustainability of global HIV/AIDS treatment.

Antiretroviral resistance patterns and factors associated with resistance in adult patients failing NNRTI‐based regimens in the western cape, South Africa

Antiretroviral drug resistance in patients failing non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐based first‐line combination antiretroviral treatment (ART) is influenced by: regimen choice, HIV‐1 subtype, detection of and response to therapy failure. In order to describe resistance patterns by genotypic testing, at the time of first‐line ART failure and to describe associations with having M184I/V, K65R, three or more thymidine analog mutations (TAMs) and etravirine (ETV) resistance, the prevalence of antiretroviral drug resistance associated mutations in a cross‐sectional study, at two South African public health clinic settings, at the time of virologic failure (HIV‐1 RNA load >400 copies/ml) are described. Also reported are associations of therapy choice, prolonged virologic failure, and concurrent HIV viral load and CD4 count with the presence of M184I/V, TAMs, K65R, and resistance to ETV. Of 167 adult patients with virologic failure on first‐line ART, 28 (17%) had no resistance, 137 (82%) had NNRTI resistance, 101 (60%) M184I/V, 20 (12%) TAMs, of which 4 had 3 or more TAMs, and 7 (4%) had K65R, of which 6 were on D4T and one on AZT. A prolonged estimated period of failure was associated with having ≥3 TAMs. Patients treated with nevirapine (NVP) were more likely to have ETV resistance than those treated with efavirenz (EFV). Major protease inhibitor mutations were not detected. A delayed response to ART failure may risk accumulation of TAMs in patients on an NNRTI‐based regimen. The use of NVP rather than EFV was associated with ETV resistance. J. Med. Virol. 83:1764–1769, 2011.

Evaluation of Paradoxical TB-Associated IRIS With the Use of Standardized Case Definitions For Resource-Limited Settings

Objective: Standardized case definitions have recently been proposed by the International Network for the Study of HIV-associated immune reconstitution inflammatory syndrome (INSHI; [IRIS]) for use in resource-limited settings. We evaluated paradoxical tuberculosis (TB)-associated IRIS in a large cohort from a TB endemic setting with the use of these case definitions. Design: A retrospective cohort study. Method: We reviewed records from 1250 South African patients who initiated antiretroviral therapy (ART) over a 5-year period. Results: A total of 333 (27%) of the patients in the cohort had prevalent TB at the initiation of ART. Of 54 possible paradoxical TB-associated IRIS cases, 35 fulfilled the INSHI case definitions (11% of TB cases). Conclusions: INSHI-standardized case definitions were used successfully in identifying paradoxical TB-associated IRIS in this cohort and resulted in a similar proportion of TB IRIS cases (11%) as that reported in previous studies from resource-limited settings (8%-13%). This case definition should be evaluated prospectively.

Combination antiretroviral therapy reduces the detection risk of cervical human papilloma virus infection in women living with HIV.

Objective:Data on the effect of combination antiretroviral therapy (cART) on cervical human papilloma virus (HPV) infection are both limited and conflicting. We aimed to determine the effect of the initiation of cART for HPV genotype detection on cervical samples in HIV-infected South African women. Design:Prospective cohort study. Methods:Generalized estimating equation was performed to estimate parameters of mixed-effects logistic regression models of cART on HPV cervical detection risk, adjusting for time-dependent covariates CD4+ T-cell count, sexual activity and excision treatment. Ratio of odds ratios (ORs) was computed to compare the pooled cART effect on lower vs. high-risk HPV genotype groups, to the effect of cART on the risk of HPV-16 detection. Results:Of the 300 patients, 204 (68%) were commenced on ART during follow-up, as they met the criteria for cART initiation. cART significantly reduced the risk for detection of HPV by 77% [OR 0.23, 95% confidence interval (CI) 0.15–0.37]. cART significantly reduced the risk of HPV-16 detection (OR 0.50, 95% CI 0.37–0.67). Every month on cART significantly reduced the detection risk of any HPV type by 9% (OR 0.91, 95% CI 0.89–0.94). The protective effect of cART on the detection risk for the low-risk HPV genotype group was significantly less than the protective effect of cART on the detection risk of HPV-16 (ratio of ORs 1.35, 95% CI 1.22–1.50). Conclusion:cART significantly reduced cervical HPV infection. This effect was dependent on the duration of exposure to cART and is the mechanism by which cART may improve the outcome of dysplasia in HIV-infected women.

African-based CCR5 single-nucleotide polymorphism associated with HIV-1 disease progression.

In this study we show a statistically significant association between the CCR5-A335V SNP and decreased disease progression from HIV infection to AIDS within individuals of African ethnic origin residing in the Western Cape of South Africa. The variable penetrance observed for this protective association together with previous findings that this polymorphic marker results in a functional response similar to that of wild-type CCR5 suggests that A335V does not contribute directly in slowing disease progression. We therefore hypothesize that this genetic marker in combination with other weaker genetic events collectively acts in slowing disease progression and may ultimately contribute to providing an individual HIV susceptibility risk profile for sub-Saharan Africans. (excerpt)

Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy

December 2005, Vol. 95, No. 12 SAMJ The prognosis of patients infected with HIV type 1 has improved markedly since the advent of potent antiretroviral therapies (ARTs). ARTs have enabled sustained suppression of HIV replication, recovery of the immune system and a substantial decrease in the frequency of opportunistic infections. Antiretrovirals may, however, cause life-threatening complications which include lactic acidosis, pancreatitis, hypersensitivity reactions, liver toxicity and severe immune reconstitution inflammatory syndrome.

Impact of timing of antiretroviral therapy initiation on survival of cervical squamous intraepithelial lesions: a cohort analysis from South Africa.

To determine factors that influence excision treatment outcome and recurrence of cervical squamous intraepithelial lesions (SIL) in women living with HIV infection, we analysed 1848 women who underwent excision treatment of cervical SIL at Tygerberg Hospital, Cape Town, South Africa. We compared treatment failure defined as presence of cervical intraepithelial neoplasia (CIN) I (presence of CIN I or higher at first follow-up after excision treatment) and post-excision recurrence of lesions (at one year or later) between women of HIV-positive, -negative or unknown status and examined factors associated with excision treatment outcome and recurrence. HIV-infected women experienced higher treatment failure than uninfected women (53.8% versus 26.9%, P< 0.001). At treatment failure, more HIV-infected women had low-grade squamous intraepithelial lesion (LSIL) compared with uninfected women (64.9% versus 37.3%, P < 0.001). Treatment failure did not differ with the type of excision used in HIV-infected women. HIV-infected women were more likely to experience recurrence of lesions after excision treatment than uninfected women (hazard ratio 1.95, 95% confidence interval [CI] 1.59-2.39; P < 0.001). Antiretroviral therapy (ART) initiated before excision biopsy had a strong protective effect against recurrence (hazard ratio 0.70, 95% CI 0.55-0.89; P = 0.006). Our data suggest that women with cervical SIL initiated on ART earlier may be expected to have better long-term excision treatment outcome. Close follow-up should be maintained after cervical excision treatment, especially in a setting of high HIV prevalence.

Patterns of prevalent HPV and STI co-infections and associated factors among HIV-negative young Western Cape, South African women: the EVRI trial.

Objective To estimate the prevalence and describe the patterns of concurrent human papillomavirus (HPV) and STIs and associated factors among HIV-negative young Western Cape, South African women participating in the Efficacy of HPV Vaccine to Reduce HIV Infection (EVRI) trial. Methods HIV-negative women aged 16–24 years old were enrolled in the EVRI trial (NCT01489527) and randomised to receive the licensed four-valent HPV vaccine or placebo. At study entry, participants were clinically evaluated for five STIs: herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis and disease-causing HPV genotypes (6/11/16/18/31/33/35/39/45/51/52/56/58/59/68). Demographic and sexual history characteristics were compared among women with STI co-infections, single infection and no infection using Pearson χ2 and Mann-Whitney tests. ORs were calculated to evaluate factors associated with STI co-infection prevalence. Results Among 388 young women, STI co-infection prevalence was high: 47% had ≥2 concurrent STIs, 36% had a single STI and 17% had none of the five evaluated STIs. HPV/HSV-2 (26%) was the most prevalent co-infection detected followed by HPV/HSV-2/Chlamydia trachomatis (CT) (17%) and HPV/CT (15%). Co-infection prevalence was independently associated with alcohol use (adjusted OR=2.01, 95% CI 1.00 to 4.06) and having a sexual partner with an STI (adjusted OR=6.96, 95% CI 1.53 to 30.08). Conclusions Among high-risk young women from underserved communities such as in Southern Africa, a multicomponent prevention strategy that integrates medical and behavioural interventions targeting both men and women is essential to prevent acquisition of concurrent STI infections and consequent disease. Trial registration number NCT01489527; Post-results.

A prospective study on the outcome of human immunodeficiency virus-infected patients requiring mechanical ventilation in a high-burden setting

BACKGROUND There is a paucity of data on the mortality of patients admitted to the intensive care unit (ICU), despite the fact that human immunodeficiency virus (HIV)-related diseases represent a significant burden to health care resources particularly in sub-Saharan Africa. AIM To describe the outcome and prognostic factors of HIV-infected patients requiring mechanical ventilation in an ICU. DESIGN Prospective observational study. METHODS All 54 patients (34.8 ± 10.4 years, 38 females) admitted with confirmed HIV from October 2012 until May 2013 were enrolled. Disease severity was graded according to APACHEII score. Admission diagnoses, clinical features and laboratory investigations, complications and outcomes were recorded. RESULTS The mean length of ICU stay was 11.0 days (range: 1-49 days), and 33 patients survived (ICU mortality: 38.9%). The in-hospital mortality at 30 days was 48.1%. ICU mortality was associated with an AIDS-defining diagnosis (OR = 7.97, P = 0.003). Non-survivors had higher APACHEII scores (25.8 vs. 18.6, P = 0.001) and lower mean admission CD4 counts (102.5 vs. 225.2, P = 0.014). Multiple logistical regression analysis confirmed the independent predictive value of WHO stage 4 disease (P = 0.008), lower mean CD4 count on admission (P = 0.057) and higher APACHEII score (P = 0.010) on ICU mortality, and WHO stage 4 (P = 0.007) and higher APACHE II score (P = 0.003) on 30-day mortality. CONCLUSIONS The ICU mortality of mechanically ventilated HIV-positive patients was high. WHO stage 4 disease and a higher APACHEII score were predictive of both ICU and 30-day mortality, whereas a low CD4 count on admission was associated with ICU mortality.