Somnuek Sungkanuparph

Declining Prevalence of Drug-Resistant Tuberculosis among HIV/Tuberculosis Co-Infected Patients Receiving Antiretroviral Therapy

BACKGROUND Drug-resistant tuberculosis (DR-TB) is a serious threat in developing countries where the prevalence of both HIV and TB are high. Antiretroviral therapy (ART) has been more accessible in these countries. The present study aimed to determine the impact of ART on the prevalence of DR-TB among HIV/TB co-infected patients. MATERIAL AND METHOD A retrospective cohort study was conducted among HIV-infected patients with culture-proved TB from 1999 to 2004. Susceptibilities of Mycobacterium tuberculosis to antituberculous drugs and rate ofART use were studied. RESULTS There were 225 patients, mean age 35.8 years, 72.4% male and median CD, 44 cells/mm(3). Patients who had received ART increased from 18.5% in 1999 to 92.1% in 2004 (p<O. 001). The prevalence of DR-TB in the years 1999 and 2004 were 48% and 7.9%, respectively (p<O.001). The prevalence of isoniazid- and rifampicin-resistance significantly declined in 2004 when compared with those in 1999 (p<O. 05). CONCLUSION The declines in the prevalence of DR-TB, INH- and RFP-resistance in HIV/TB co-infected patients are possibly attributable to the use of ART In addition to the survival benefit from ART in HIV-infected patients, increasing use of ART among HIV-infected patients may eliminate DR-TB in this population.

Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy.

Background: The impact of antiretroviral therapy (ART) on survival among patients coinfected with HIV and tuberculosis (TB) has not been well established. Methods: A retrospective cohort study was conducted among HIV-infected patients with TB between January 2000 and December 2004. Patients were categorized into ART+ group (received ART) and ART− group (did not receive ART) and were followed until April 2005. Results: A total of 1003 patients were identified; 411 in ART+ group and 592 in ART− group. Median (interquartile range) CD4 count was 53 (20-129) cells/mm3. Survival rates at 1, 2, and 3 years after TB diagnosis were 96.1%, 94.0%, and 87.7% for ART+ group and 44.4%, 19.2%, and 9.3% for ART− group (log-rank test, P < 0.001). Cox proportional hazard model showed that ART was associated with lower mortality rate; gastrointestinal TB and multidrug resistant TB were associated with higher mortality rate (P < 0.05). Among patients in ART+ group, the patients who delayed ART ≥6 months after TB diagnosis had a higher mortality rate than those who initiated ART <6 months after TB diagnosis (P 0.018, hazard ratio = 2.651, 95% confidence interval = 1.152-6.102). Conclusions: Antiretroviral therapy substantially reduces mortality rate among HIV/TB-coinfected patients. Initiation of ART within 6 months of TB diagnosis is associated with greater survival.

Options for a Second-Line Antiretroviral Regimen for HIV Type 1-Infected Patients Whose Initial Regimen of a Fixed-Dose Combination of Stavudine, Lamivudine, and Nevirapine Fails

BACKGROUND A fixed-dose combination of stavudine, lamivudine, and nevirapine is extensively used as an antiretroviral regimen in developing countries because of its affordability. Virological failure with this regimen has become more common, and a second-line regimen needs to be prepared in the national program. METHODS Genotypic resistance testing was conducted among human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced treatment failure with their first antiretroviral regimen (a fixed-dose combination of stavudine, lamivudine, and nevirapine) during 2003-2005. Patterns of resistance mutations and options for a second-line regimen were studied. RESULTS We studied 98 patients (mean age, 35.2 years), of whom, 63% were male. The median duration of antiretroviral therapy was 20 months. The median HIV-1 RNA load at the time of virological failure detection was 4.1 log copies/mL. The prevalences of patients with > or =1 major mutation conferring drug resistance to nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors were 95% and 92%, respectively. M184V was the most common nucleoside reverse-transcriptase inhibitor resistance mutation (observed in 89% of patients). Thymidine analogue mutations, K65R, and Q151M were observed in 37%, 6%, and 8% of patients, respectively. Patients with an HIV-1 RNA load of >4 log copies/mL at the time of treatment failure had higher prevalence of thymidine analogue mutations (P=.041), K65R (P=.031), and Q151M (P=.008) mutations. The second-line regimen was determined in a resource-limited setting where tenofovir and enfuvirtide are not available; the options were limited for 48% of patients. CONCLUSIONS After experiencing treatment failure with a fixed-dose combination of stavudine, lamivudine, and nevirapine, almost all patients have lamivudine and nonnucleoside reverse-transcriptase inhibitor resistance. The options for a second-line regimen are limited for one-half of these patients. In resource-limited settings where availability of antiretroviral agents is limited, strategies for prevention of HIV-1 resistance are crucial. Early detection of virological failure may provide more options and better treatment outcomes.

Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions

Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.

HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients.

Objective Investigation of a possible involvement of differences in human leukocyte antigens (HLA) in the risk of nevirapine (NVP)-induced skin rash among HIV-infected patients. Methods A step-wise case–control association study was conducted. The first set of samples consisted of 80 samples from patients with NVP-induced skin rash and 80 samples from NVP-tolerant patients. These patients were genotyped for the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 by a sequence-based HLA typing method. Subsequently, we verified HLA alleles that showed a possible association in the first screening using an additional set of samples consisting of 67 cases with NVP-induced skin rash and 105 controls. Results An HLA-B*3505 allele revealed a significant association with NVP-induced skin rash in the first and second screenings. In the combined data set, the HLA-B*3505 allele was observed in 17.5% of the patients with NVP-induced skin rash compared with only 1.1% observed in NVP-tolerant patients [odds ratio (OR)=18.96; 95% confidence interval (CI)=4.87–73.44, Pc=4.6×10−6] and 0.7% in general Thai population (OR=29.87; 95% CI=5.04–175.86, Pc=2.6×10−5). The logistic regression analysis also indicated HLA-B*3505 to be significantly associated with skin rash with OR of 49.15 (95% CI=6.45–374.41, P=0.00017). Conclusion A strong association between the HLA-B*3505 and NVP-induced skin rash provides a novel insight into the pathogenesis of drug-induced rash in the HIV-infected population. On account of its high specificity (98.9%) in identifying NVP-induced rash, it is possible to utilize the HLA-B*3505 as a marker to avoid a subset of NVP-induced rash, at least in Thai population.

Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals

Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.

Undetectable Plasma HIV RNA Load Predicts Success after Hepatitis B Vaccination in HIV-Infected Persons

Human immunodeficiency virus (HIV)-infected patients respond poorly to hepatitis B vaccination. Records of 194 HIV-infected patients were reviewed for factors associated with successful hepatitis B vaccination. Thirty-four patients (17.5%) developed a protective antibody response. In a logistic regression model, only a plasma HIV RNA level of <400 copies/mL at the time of vaccination was associated with a protective antibody response (P=.003).

Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Discontinuation of Secondary Prophylaxis for Cryptococcal Meningitis in Human Immunodeficiency Virus-Infected Patients Treated with Highly Active Antiretroviral Therapy: A Prospective, Multicenter, Randomized Study

A prospective, multicenter, randomized study was conducted with human immunodeficiency virus (HIV)-infected patients who were successfully treated for acute cryptococcal meningitis, were receiving secondary prophylaxis, and were naive for antiretroviral therapy. Patients were randomized to continue or discontinue secondary prophylaxis when the CD4 cell count had increased to >100 cells/microL and an undetectable HIV RNA level had been sustained for 3 months. At a median of 48 weeks after randomization, there were no episodes of cryptococcal meningitis in either group.

A Randomized Trial Comparing Plasma Drug Concentrations and Efficacies between 2 Nonnucleoside Reverse-Transcriptase Inhibitor-Based Regimens in HIV-Infected Patients Receiving Rifampicin: The N2R Study

BACKGROUND To our knowledge, to date, no prospective, randomized, clinical trial has compared standard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis (TB) who are receiving rifampicin. METHODS Rifampicin recipients with concurrent HIV-1 infection and TB were randomized to receive antiretroviral therapy that included either efavirenz (600 mg per day) or nevirapine (400 mg per day). Efavirenz and nevirapine concentrations at 12 h after dosing (C12) were monitored at weeks 6 and 12. CD4+ cell counts and HIV-1 RNA levels were assessed every 12 weeks. RESULTS One hundred forty-two patients were randomized into 2 groups equally. The mean body weight of patients was 53 kg, the mean CD4+ cell count was 65 cells/mm3, and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12, the mean C12 of efavirenz (+/- standard deviation) were 4.27+/-4.49 and 3.54+/-3.78 mg/L, respectively, and those for nevirapine were 5.59+/-3.48 and 5.6+/-2.65 mg/L, respectively. Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group (coefficient of variation, 107% vs. 47%). At week 12, 3.1% of patients in the efavirenz group and 21.3% in the nevirapine group had C12 values that were less than the recommended minimum concentrations (odds ratio, 8.396; 95% confidence interval, 1.808-38.993; P= .002). Intention-to-treat analysis revealed that 73.2% and 71.8% of patients in the efavirenz and nevirapine groups, respectively, achieved HIV-1 RNA levels <50 copies/mL at week 48, with respective mean CD4+ cell counts of 274 and 252 cells/mm3 (P> .05). Multivariate analysis revealed that patients with low C12 values and those with a body weight <55 kg were 3.6 and 2.4 times more likely, respectively, to develop all-cause treatment failure (P< .05). CONCLUSIONS Antiretroviral therapy regimens containing efavirenz (600 mg per day) were less compromised by concomitant use of rifampicin than were those that contained nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB. Low drug exposure and low body weight are important predictive factors for treatment failure.