M.E. van der Ende

The AmRo study: pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery.

Objective  To explore pregnancy outcome in HIV‐1‐positive and HIV‐negative women, and mother‐to‐child transmission (MTCT) according to mode of delivery under effective highly active antiretroviral therapy (HAART).

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

ObjectiveTo assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1-infected patients. DesignA multicentre, open-label, randomized controlled trial. MethodsA total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. ResultsThe median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. ConclusionRTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication

High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they were approximately 2-fold higher than reported IC50 values of resistant virus.

Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort

INTRODUCTION With the introduction of HAART, the HIV-1 has turned from a lethal into a chronic infection in the majority of patients. In homosexual populations, 20% of HIV-1 infected patients suffer from a chronic HBV infection, which may eventually lead to complications of the liver disease because of prolonged survival. Lamivudine is effective in reducing both HIV-1 and HBV viral replication. However, resistance for lamivudine may complicate the course of the HBV disease in HIV-1-infected patients. We, therefore, conducted a retrospective study in HIV-1-HBV co-infected patients on lamivudine therapy. PATIENTS AND METHODS All HIV-1-HBV co-infected patients who were treated with lamivudine for over 6 months in five major referral clinics in The Netherlands with HBV DNA above 2.0 x 10(5) geq ml(-1) at baseline, were evaluated. Retrospectively, the course of HBV DNA in available serum samples was established. If HBV DNA was detectable with the sensitive PCR-assay, YMDD-analyses of the polymerase gene of the hepatitis B virus was executed with the INNO-LiPA-DR-strip. RESULTS Forty-six patients were evaluated. The median level of HBV DNA at start of lamivudine therapy was 1.31 x 10(9) geq ml(-1) (range 3.5 x 10(5) - 2.0 x 10(10), n=43). Of three patients no baseline sample was available, but since HBV DNA was still above 2.0 x 10(5) geq ml(-1) at week 3, 7 and 11, these patients were included. Median duration of lamivudine therapy was 97 weeks (range 27-263). The percentage of detected mutations was 25 and 52% at 1 and 2 years, respectively. Twenty-two patients ultimately developed a mutation. Both baseline Body Mass Index (BMI) and the decrease in CD4 cell count as a time dependent factor were significantly related to the emergence of mutations. In 10 out of 12 evaluated patients, HBV DNA levels returned to baseline level or even above baseline level after the development of mutant virus. One patient (5%) developed a flare of serum transaminases (ALT>10 x ULN) 24 weeks after first detection of variant virus. CONCLUSION There is a linear time-dependent appearance of HBV mutations for lamivudine in our population. In a minority of patients (5%), development of a mutation was followed by a significant elevation of serum transaminases. A decline in CD4 cell count, which may indicate less response to HAART, induces a faster emergence of mutations and close surveillance of HBV co-infected patients on therapy may be indicated due to the prolonged survival of HIV-1 patients.

The effect of treatment intensification in HIV-infection : A study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine

ObjectiveTo evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/stavudine (D4T) or RTV/SQV alone, with treatment intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. DesignMulticentre, open-label, randomized controlled trial. Two-hundred and eight patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks. ResultsIn a strict intention-to-treat analysis, counting all dropouts as virological failures, 63% [95% confidence interval (CI), 54–73%] of subjects in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week 48, as compared with 69% (95% CI, 60–78%) in the RTV/SQV/D4T group (n = 104;P = 0.379). In the on-treatment analysis these percentages were 88 and 91% respectively. Thirty-one patients intensified their study medication according to the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events. ConclusionThe concept of starting with a simple, potent regimen, that could be intensified if necessary, showed good virological results after 48 weeks in this study, comparable to starting with more drugs from the beginning. Longer follow-up is needed to determine the long-term efficacy of this treatment strategy.

Associations between ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles in relation to efavirenz and nevirapine pharmacokinetics in HIV-infected individuals.

Background Human immunodeficiency virus (HIV)-infected individuals show large interindividual variation in response to antiretroviral therapy. Efavirenz (EFV) and nevirapine (NVP) are nonnucleoside reverse transcriptase inhibitors, which are prescribed in combination with other antiretroviral therapy in so-called highly active antiretroviral therapy. Recent studies provide evidence for the role of cytochrome P450 (CYP) genes, in particular CYP2B6, in relation to EFV and NVP pharmacokinetics. In this study, the authors investigated whether common ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 alleles are associated with plasma concentrations of EFV and NVP in HIV-infected individuals. Methods Plasma drug concentrations were quantified by high-performance liquid chromatography in 143 HIV-infected individuals receiving either EFV or NVP. Genotyping for common alleles was performed by restriction fragment length polymorphism and Taqman assays. Individuals were genotyped for 11 single-nucleotide polymorphisms in 5 genes. CYP2B6 haplotypes were reconstructed by PHASE. Results Plasma EFV concentrations were positively associated with CYP2B6 c.516G>T, c.785A>G, and c.983A>G single-nucleotide polymorphisms in HIV-infected individuals. Increased plasma concentrations of EFV and NVP were present in individuals with the CYP2B6*6/*6 or *6/*18 haplotype compared with CYP2B6*1/*1 [increase of 62% (95% confidence interval, 44.0–80.1) and 24% (95% confidence interval, 7.0–40.0), respectively, P < 0.01]. No significant association with other genes in relation to EFV or NVP concentrations was found. Conclusions In this study, a strong association of CYP2B6*6 and CYP2B6*18 alleles in relation to EFV and NVP plasma concentrations was found, which confirmed previous studies.

Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study

Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0–52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63–15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04–12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02–6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27–192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39–8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19–2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60–14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM.

Risk factors and outcome of HIV‐associated idiopathic noncirrhotic portal hypertension

Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection.

Differential CD4 T‐cell response in HIV‐1‐infected patients using protease inhibitor‐based or nevirapine‐based highly active antiretroviral therapy

To study the dynamics of CD4 T‐lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)‐based or nevirapine (NVP)‐based first‐line highly active antiretroviral therapy (HAART).

Papillary Necrosis Associated with the HIV Protease Inhibitor Indinavir

The HIV protease inhibitor indinavir may cause nephrolithiasis and interstitial nephritis. The renal consequences of indinavir-associated nephrotoxicity are uncertain. We report a case of papillary necrosis in a patient treated with indinavir.An asymptomatic HIV-infected woman experienced right-sided renal colicky pain during treatment with indinavir. She passed a non-solid stone and continued indinavir treatment. Intravenous pyelogram performed 20 months later following an episode of left-sided colicky pain showed right-sided papillary necrosis. Indinavir-associated nephrolithiasis and chronic interstitial nephritis were the only possible causes identified in this patient. Physicians should be aware that indinavir nephrolithiasis may cause papillary necrosis.