Dose Of Nevirapine Research Articles

A single peripartum dose of nevirapine is associated with subsequent virologic failure of nevirapine-based antiretroviral therapy

A single peripartum dose of nevirapine is associated with subsequent virologic failure of nevirapine-based antiretroviral therapy

A Randomized, Double‐Blind, Placebo‐Controlled Trial of Combined Nevirapine and Zidovudine Compared with Nevirapine Alone in the Prevention of Perinatal Transmission of HIV in Zimbabwe

A single dose of nevirapine (sdNVP) administered to both mother and infant can decrease mother-to-child transmission of human immunodeficiency virus (HIV) by 47%, compared with ultra-short course zidovudine therapy (usZDV). There is limited data about the benefit of usZDV added to sdNVP to prevent mother-to-child transmission. We performed a double-blind, randomized, placebo-controlled trial to determine whether usZDV combined with sdNVP improved neonatal outcome, compared with sdNVP alone. Mothers were randomized to 1 of 2 treatment groups. Mothers in the usZDV/sdNVP group received a loading dose of zidovudine (600 mg administered orally) and continued to receive 300-mg doses of zidovudine orally every 3 h while in labor, and their infants received zidovudine at a dosage of 2 mg per kg of body weight 4 times per day orally for 72 h. Mothers and infants in the sdNVP group received zidovudine placebo dosed in the same manner. All mothers also received nevirapine at a dosage of 200 mg orally while in labor, and all infants received nevirapine 2 mg per kg of body weight orally within 72 h of delivery. The study was stopped on the basis of futility, because interim data showed that, at present trends, superiority would not be demonstrated. Results at 6 weeks of age were available for 609 infants. The primary end point of HIV RNA positivity or death occurred in 21.8% of infants in the usZDV/sdNVP arm and 23.6% of the infants in the sdNVP arm. usZDV, when added to a standard 2-dose regimen of sdNVP, did not demonstrate a clinically important decrease in the combined end point of mother-to-child transmission or infant death. High rates of adverse maternal and infant outcome in both study arms suggest that improved approaches are necessary.

Brief Report: Enzyme Inducers Reduce Elimination Half-Life After a Single Dose of Nevirapine in Healthy Women

Single-dose nevirapine (SD-NVP) to prevent mother-to-child transmission (MTCT) of HIV is associated with development of NVP resistance, probably because of its long half-life in combination with a low genetic barrier to resistance. The objective of this study was to find enzyme inducers to reduce the NVP half-life. The design of this phase 1 pharmacokinetic study was a single-center, open-label, 2-period, 9-group study. After administration of a single 200-mg dose of NVP to HIV-seronegative nonpregnant women in periods 1 and 2, blood was sampled twice a week for 21 days. In period 2, additional interventions (single-dose carbamazepine, phenobarbital, or phenytoin; phenytoin for 3 or 7 days; or St. John's wort, vitamin A, or cholecalciferol for 14 days) were administered to all subjects except for the control group. Thirty-six subjects participated. In 3 intervention groups, the T-half ratio (nevirapine half-life in period 2/half-life in period 1) differed significantly from that in the control group: a single 400-mg dose of carbamazepine (P = 0.021) or 184 mg of phenytoin once daily for 3 (P = 0.021) or 7 days (P = 0.021). The median decreases in the NVP half-life were 18.8, 19.0, and 16.9 hours, respectively. Interventions with a single dose of 400 mg of carbamazepine or 184 mg of phenytoin for 3 or 7 days effectively reduced the NVP half-life. Appropriately powered safety and feasibility end point studies are warranted before these interventions can be tested in the setting of single-dose NVP for prevention of mother-to-child transmission (PMTCT) of HIV to reduce the development of NVP resistance.

Long‐term assessment of nevirapine‐containing highly active antiretroviral therapy in antiretroviral‐naive HIV‐infected patients: 3‐year follow‐up of the VIRGO study

Data on the durability of antiretroviral regimens over a 3-year period have only rarely been reported. The aim of this study was to evaluate the long-term efficacy and safety of one or two daily doses of nevirapine (NVP), in combination with stavudine (d4T) and didanosine (ddI), in HIV-infected patients. This study was a follow-up of the VIR (amune) Grand Ouest (VIRGO) study, a 12-month open-label trial to assess the safety and immunovirological activity of NVP-d4T-ddI combination therapy in antiretroviral-naive HIV-1-infected adults with baseline CD4 counts > or =200 cells/microL and plasma viral loads > or =5000 HIV-1 RNA copies/mL. Of the 100 patients included in the study, the 67 patients remaining on the initial triple therapy at the end of the study (1 year) were offered an extra 24 months of follow-up. Of the 60 patients who extended follow-up, 46 were still being treated with d4T-ddI-NVP at month 36; 91% (39/43) had a plasma viral load <500 copies/mL (data were missing for three patients). CD4 cell counts increased over 36 months. Safety and tolerance were good with no unexpected long-term toxicity. After 3 years of treatment with NVP-d4T-ddI, nearly half of the patients were still receiving the initial antiretroviral therapy with a sustained and durable immunovirological benefit. Long-term toxicity was mainly related to the nucleoside reverse transcriptase inhibitor components of the regimen.

Quantitative Analysis of HIV-1 Variants With the K103N Resistance Mutation After Single-Dose Nevirapine in Women With HIV-1 Subtypes A, C, and D

We used a sensitive point mutation assay, LigAmp, to detect and quantify K103N-containing variants in African women who received single-dose nevirapine (NVP) to prevent mother-to-child HIV-1 transmission. Plasma for testing was collected 6 to 8 weeks postpartum from 301 women (144 subtype A, 63 subtype C, and 94 subtype D). The portion of women with 0.5% or more K103N-containing variants was lowest for subtype A (60/144, 41.7%) and highest for subtype C (44/63, 69.8%; P < 0.0001). K103N was rarely detected in pre-NVP samples. In a multivariate model, K103N detection was associated with HIV-1 subtype (C > A), after adjusting for log10 delivery viral load, the number of days between NVP dosing and sample collection, age, and parity. Among women with K103N detected: (1) the median %K103N was lower for subtype A (2.2%) than C (11.7%, P = 0.0001) or D (5.5%, P = 0.04), and (2) in a multivariate linear model, higher log10 (%K103N) was associated with HIV subtype (C > A, P = 0.0001; D > A, P = 0.01; and C vs D, no difference), but not other factors. After administration of single-dose NVP, K103N was detected more frequently and at higher levels in women with subtypes C and D than A. Further studies are needed to evaluate the clinical significance of NVP-resistant variants in this setting.

ERRATUM

Introduction: We used a sensitive point mutation assay, LigAmp, to detect and quantify K103N-containing variants in African women who received single-dose nevirapine (NVP) to prevent mother-to-child HIV-1 transmission. Methods: Plasma for testing was collected 6 to 8 weeks postpartum from 301 women (144 subtype A, 63 subtype C, and 94 subtype D). Results: The portion of women with 0.5% or more K103N-containing variants was lowest for subtype A (60/144, 41.7%) and highest for subtype C (44/63, 69.8%; P < 0.0001). K103N was rarely detected in pre-NVP samples. In a multivariate model, K103N detection was associated with HIV-1 subtype (C > A), after adjusting for log10 delivery viral load, the number of days between NVP dosing and sample collection, age, and parity. Among women with K103N detected: (1) the median %K103N was lower for subtype A (2.2%) than C (11.7%, P = 0.0001) or D (5.5%, P = 0.04), and (2) in a multivariate linear model, higher log10 (%K103N) was associated with HIV subtype (C > A, P = 0.0001; D > A, P = 0.01; and C vs D, no difference), but not other factors. Conclusions: After administration of single-dose NVP, K103N was detected more frequently and at higher levels in women with subtypes C and D than A. Further studies are needed to evaluate the clinical significance of NVP-resistant variants in this setting.

Comparison of HIV-1 Mother-to-Child Transmission After Single-Dose Nevirapine Prophylaxis Among African Women With Subtypes A, C, and D

The HIVNET 012 trial in Uganda showed that mother-to-child transmission (MTCT) of HIV-1 can be prevented by providing pregnant women and their infants with a single dose (SD) of the antiretroviral drug nevirapine (NVP). Safety and efficacy of 1- or 2-dose NVP prophylaxis for prevention of MTCT have been documented in other studies. We have shown that NVP resistance emerges in some women after SD NVP prophylaxis and that the portion of women with NVP resistance is influenced by HIV-1 subtype. At 6 to 8 weeks after SD NVP NVP resistance was more common in women with subtype C (69.2%) than in women with subtype D (36.1% P < 0.0001) or subtype A (19.4% P < 0.0001).4 Selection of NVP-resistant HIV-1 variants in women after NVP dosing could theoretically lower the efficacy of NVP prophylaxis for prevention of HIV transmission by breast-feeding in the first few weeks after birth. In the HIVNET 012 trial most women were infected with HIV-1 subtype A or D. Risk of MTCT was slightly (but not statistically) higher in women with subtype D. In this report we combined data from the HIVNET 012 and NVAZ trials to compare the risk of MTCT in women with subtype C to the risk of MTCT in women with subtypes A and D in the setting of SD NVP prophylaxis. (excerpt)

Emergence of Drug Resistant HIV-1 After Intrapartum Administration of Single-Dose Nevirapine Is Substantially Underestimated

Purpose of the Study. An inexpensive, effective regimen to prevent perinatal HIV transmission in the developing world is highly desirable. Nevirapine, a nonnucleoside reverse transcriptase inhibitor, seems to provide such an intervention. However, drug-resistance mutations have been identified in up to 40% of women shortly after they received a single intrapartum nevirapine dose as part of a transmission-prevention strategy. This study was undertaken to reexamine the incidence of drug-resistant HIV-1 after single-dose nevirapine. Study Population. Fifty South African women infected with HIV subtype C. Methods. Sensitive, real-time polymerase chain reaction assays were sequentially performed for nonnucleoside reverse transcriptase inhibitor–resistance mutation, K103N and Y181C. Results. Resistance mutations emerged in 65% of women after a single dose of nevirapine. Conclusions. Single-dose nevirapine as used in the developing world for prevention of perinatal HIV transmission results in the development of resistance mutations in a very high percentage of women who receive this intervention. Reviewer Comments. Although single-dose nevirapine has been successfully implemented as a strategy to prevent perinatal HIV transmission, it is increasingly apparent that the women who are treated with this regimen more often than not develop resistance mutations to nevirapine. The clinical implications are clear: Will nevirapine work for future perinatal interventions for individual women with drug-resistance mutations? Will women with these drug-resistance mutations fail to respond to nevirapine as part of a highly active retroviral therapy intervention when they need treatment for their own HIV disease? In the same issue of The Journal of Infectious Diseases, Flys et al (J Infect Dis. 2005;192:24–29) demonstrated that drug-resistance variants of HIV may persist for &amp;gt;1 year in this situation. In addition, Lee et al (J Infect Dis. 2005;192:1260–1264) showed that women who developed drug-resistant HIV after exposure to single-dose nevirapine shed drug-resistant HIV in their breast milk. This increases the risk of transmission of resistant virus to uninfected infants. Together, these studies demonstrate that single-dose nevirapine, although an effective strategy for reducing maternal-child transmission of HIV, also predisposes treated women to the development of drug-resistant virus as well as the potential for transmitting drug-resistant virus to their infants via breastfeeding.

HIV resistance to non-nucleoside reverse transcriptase inhibitors

Resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) has been found to develop rapidly after initiation of NNRTI therapy with high level of phenotypic resistance and large cross-resistance to all licensed NNRTI. NNRTI-selected mutations confer little damage to viral fitness and persist in absence of drug. In HIV-1 non-B subtype, resistance profile could differ and survey is needed. Single dose of nevirapine in the prevention of HIV mother-tochild transmission was associated with selection of resistance and loss of virologic response to NNRTI including-regimen. Furthermore, with continued therapy, viral evolution persists, creating species with greater numbers of mutations and higher level of phenotypic resistance that limits future treatment options.Absence of immunologic and virologic effect when NNRTI interruption was proposed in patients with resistant virus suggest that these compounds have lost all their in vivo antiviral activity. Taken together, strong consideration should be given to discontinuing NNRTI after virologic failure is confirmed.

Immunoprophylaxis against Mother-to-Child Transmission of HIV-1

In resource-limited settings, there is a high risk of mother-to-child-transmission (MTCT) of HIV-1. The rate of MTCT without specific intervention and with an extended time of breast-feeding is about 35%–40% [ 1], a figure that results in the infection of about 750,000 children every year worldwide [ 2]. A single dose of nevirapine can reduce the rate of MTCT by 42%, but it selects for drug-resistant variants in as many as 75% of mothers receiving this treatment [ 3]. As multiple-drug treatment is rarely available in developing countries, and breast-feeding often continues for at least two years after delivery, the concept of preventing MTCT transmission by passive administration of antibodies, by the use of antibodies and drugs, or by the use of combined active–passive immunization is attracting increasing attention [ 4].

Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana

Single-dose nevirapine given to women and infants reduces mother-to-child HIV transmission, but nevirapine resistance develops in a large percentage of women. To determine whether the maternal nevirapine dose could be eliminated in the setting of zidovudine prophylaxis. A 2 x 2 factorial, randomized, clinical trial, with a double-blinded peripartum factor designed to assess the equivalence of maternal single-dose nevirapine versus placebo with respect to HIV transmission. A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana, resulting in 694 live first-born infants. HAART was available for women with AIDS. All women received a background of zidovudine from 34 weeks' gestation through delivery, and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor. The primary endpoint was infant HIV infection by the 1-month visit. Of the 694 infants in this equivalence study, 15 (4.3%) of 345 in the maternal nevirapine arm were HIV infected by 1 month, versus 13 (3.7%) of 349 in the maternal placebo arm (95% confidence interval for difference, -2.4% to 3.8%), meeting pre-determined equivalence criteria. Nevirapine resistance at 1 month postpartum was detected in 45% of a random sample of women who received nevirapine. In the setting of maternal zidovudine and infant zidovudine plus single-dose nevirapine, infant HIV infection rates were similar whether women received single-dose nevirapine or placebo. This strategy avoids the potential for maternal nevirapine resistance.

Increasing Nevirapine Dose Can Overcome Reduced Bioavailability Due to Rifampicin Coadministration

We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 microg/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 microg/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

This is no time to stop use of nevarapine to prevent mother-to-child transmission of HIV

In a recent paper in AIDS Chi et al. reported a secondary analysis of data from HIVNET 024 that addressed the importance of timing of maternal and infant nevirapine (NVP) dosing in preventing mother-to-child transmission (MTCT) of HIV. Their analysis extended the documentation of the marked success of this strategy in preventing intrapartum/early postnatal transmission of HIV in low-resource areas. Yet despite these gains in some areas of Zambia one third of HIV infected pregnant women did not take single-dose NVP during labour. Three reports of MTCT in 2005 at the Twelfth Conference on Retroviruses and Opportunistic Infections in Boston (DITRAME+ DREAM and MASHI) documented a further and dramatic reduction in vertical transmission of HIV to < 5%. (excerpt)

Association between the Replication Capacity and Mother‐to‐Child Transmission of HIV‐1, in Antiretroviral Drug–Naive Malawian Women

Replication capacity and transmission of human immunodeficiency virus (HIV)-1 in antiretroviral drug-naive Malawian women who had subtype C infection were investigated. Infant children of these women received either 1 dose of nevirapine or 1 dose of nevirapine plus 1 week of daily doses of zidovudine. PhenoSense HIV was used to determine replication capacity in 49 women whose infants were infected with HIV-1 and in 47 women whose infants were uninfected by 6-8 weeks of age. Mean replication capacity was higher in transmitters than in nontransmitters (P=.01). In a multivariate model, higher replication capacity was associated with transmission (odds ratio, 1.45 for each 10% increase in replication capacity [95% confidence interval, 1.11-1.90]; P = .0063), after adjustment for maternal HIV-1 load and other factors.

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. Two reviewers independently assessed the methodological quality of the trials and extracted data. Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Controversies in the use of nevirapine for prevention of mother-to-child transmission of HIV

The use of nevirapine to prevent mother-to-child transmission of HIV has been controversial. Claims of high rates of toxicity have not been confirmed in clinical trials or extensive programme experience of use of the regimen. Whilst single-dose nevirapine can reduce transmission rates to ∼ 10 – 15%, this can be halved by the addition of single-dose nevirapine to short-course regimens of zidovudine. The selection of resistant virus is reported in 20 – 50% of mothers and 50% of infants following one dose of nevirapine, although the impact of this on future treatment options is not fully understood. An increased risk of severe hepatotoxicity has been reported with long-term nevirapine-containing triple-therapy treatment regimens in women with CD4+ counts > 250 cells/mm3.

Strategies to prevent mother-to-child transmission of HIV

This review describes recent advances in the prevention of mother-to-child transmission, focusing on the use of antiretroviral treatment strategies in pregnancy, and discusses the emergence of viral resistance following the use of nevirapine to prevent mother-to-child transmission. Mother-to-child transmission has been dramatically reduced in developed countries by the use of antiretroviral treatment and avoidance of breastfeeding. Highly active antiretroviral therapy use in pregnancy is recommended for women who require ongoing treatment, and, where available, is also very effective in reducing mother-to-child transmission in women with higher CD4 counts. The addition of a maternal and infant nevirapine dose to antenatal zidovudine can reduce transmission to below 5%, approximately half the transmission rate that can be achieved by single-dose nevirapine alone. The emergence of resistant virus following nevirapine use is a concern, occurring in up to 60% of mothers and 50% of infants following a single dose. Addition of zidovudine and lamivudine for 4-7 days postpartum can reduce the risk of resistance to 10%. There is broad consensus on an approach to preventing mother-to-child transmission, which provides antiretroviral treatment in pregnancy and beyond to those women who need it, and an effective prophylactic regimen for those who do not yet need treatment, These regimens include highly active antiretroviral therapy, where available, a zidovudine-plus-nevirapine regimen in other settings, or nevirapine alone where this is all that is possible. More work is needed on the impact of nevirapine resistance and on reducing breast-milk transmission.

Antiretroviral Therapy for Prevention of Mother-to-Child HIV Transmission

Administration of potent antiretroviral combination therapy in the second and third trimester of pregnancy and during delivery, and for 6 weeks postpartum to the infant, may reduce HIV transmission from the mother to the child to <2% in formula-fed infants. In resource-constrained settings where women have limited access to antenatal care, use of shorter and more practical regimens, including nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-NRTIs (NNRTIs) commenced later in pregnancy, has demonstrated efficacies ranging from 18% to 70% in breast- and bottle-fed populations. Because shorter interventions include regimens such as single-dose nevirapine or zidovudine monotherapy, which do not provide maximal suppression of viral replication, emergence of resistant mutations in mother and infant occurs frequently, primarily after exposure to drugs with low genetic barriers (i.e. those requiring only one genotypic mutation to develop resistance), such as nevirapine. Different studies have reported nevirapine resistance rates ranging from 25% to 69% in mothers receiving single-dose nevirapine alone. Because NNRTI-based combinations of antiretroviral agents are recommended as first-line therapy in countries where single-dose nevirapine is the main option for preventing mother-to-child transmission of HIV, concerns have been raised as to whether single-dose nevirapine prophylaxis can compromise the efficacy of subsequent NNRTI-based antiretroviral therapy regimens. However, although some studies have shown that nevirapine exposure may impact on short-term virological outcome, the clinical relevance of nevirapine resistance remains unclear, especially in women who start treatment >6 months after delivery or in those who are not severely immunocompromised. Furthermore, studies have shown that adding short-course (up to 7 days) zidovudine or zidovudine/lamivudine prophylaxis after delivery may dramatically reduce the occurrence of nevirapine resistance in both mothers and infants. Until data are available that allow a better understanding of the relevance of antiretroviral drug resistance acquired as a result of mother-to-child HIV transmission prophylaxis, women and children who have previously received single- dose nevirapine as part of a mother-to-child transmission prevention strategy should be considered eligible for NNRTI-based regimens and should not be denied access to antiretroviral therapy.

Rat CYP3A and CYP2B1/2 have no role in nevirapapine induced hepatotoxicity

Nevirapine is an antiretroviral drug that is used for treatment as well as for the prevention of mother-to-child transmission of the human immunodeficiency virus (HIV). Unfortunately, its adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have hampered the use of nevirapine. Since nevirapine-induced hepatotoxicity commonly occurs between 2-12 weeks of treatment, and nevirapine is a known inducer of human CYP3A and CYP2B6 isozymes, it was envisaged that the hepatotoxicity was due to activation of nevirapine to toxic metabolites by the induced enzymes. Therefore, the aim of this study was to use a rat model and determine the role of the rat analogues, rat CYP3A and CYP2B1/2, in nevirapine-induced hepatotoxicity. This was tested by the extent at which hepatotoxicity could be prevented when ketoconazole or thiotepa, known inhibitors of CYP3A and CYP2B1/2, respectively, were given one hour prior to administration of a hepatotoxic dose of nevirapine. It was shown here that nevirapine-induced hepatotoxicity only occurred in animals that were pretreated with an enzyme inducer (dexamethasone or nevirapine); that ketoconazole and thiotepa did not prevent the occurrence of nevirapine-induced hepatotoxicity; and that histopathologic examinations were more accurate than the use of liver enzymes in detecting the liver damage. This suggested that nevirapine-induced hepatotoxicity is closely associated with enzyme induction, and that liver function tests alone might not be good markers for determining nevirapine-induced hepatotoxicity. In conclusion, rat CYP3A and CYP2B1/2 may not be involved in the pathogenesis of nevirapine-induced hepatotoxicity, suggesting that a different enzyme inducible by nevirapine or dexamethasone may be responsible. However, this is yet to be proven in humans.

Characterization of drug-resistance mutations in HIV-1 isolates from non-HAART and HAART treated patients in Burkina Faso

Non-B HIV subtypes have been estimated to account for 88% of HIV infections in the world. These subtypes are particularly relevant in view of the availability of antiretroviral (ARV) drugs, since subtype-specific mutations are associated with drug-resistance in developing countries. Therefore, the pol gene sequences in HIV-1 isolates were examined from the three distinct groups of 39 infected patients from Ouagadougou in Burkina Faso: 17 patients who had not received any antiretroviral therapy (ART); 16 patients received ART, and 6 HIV-infected children, from infected mothers, received a single Nevirapine dose prophylaxis during birth. HIV-1 pol sequencing was successful for 29 samples. As expected, all patients presented the common (non-B subtype) M36I polymorphism and 26/29 (90%) the K20I mutation. Phylogenetic studies showed high predominance of recombinant HIV-1 strains: CRF06_cpx 16/29 (55.17%), CRF02_AG 9/29 (31.03%), A1 2/29 (6.89%), G 1/29 (3.44%), and CRF09_cpx 1/29 (3.44%). Two twins showed, 6 months after birth, a NNRTI-mutation (Y181C/Y). During the same period, the twin mother presented a different NNRTI-mutation (V106I), thus suggesting that the different blood drug concentration may determine a different drug-resistance pathway. Among 17 non-highly active antiretroviral therapy (HAART) patients, 3/17 (17.64%) presented virus with reverse transcriptase (RT) mutations [V118I: 1/17 patients (5.88%), V179E: 2/17 patients (11.76%)]. 10/17 (58.82%) presented virus with minor protease (PR) mutations [L63P: 5/17 patients (29.41%), V77I: 3/17 patients (17.64%), L10I: 2/17 patients (11.76%)]. 4/17 patients did not show any PR and RT mutations (23.52%). Among six HAART-treated patients, 6/6 and 3/6 had M36I and L63LP protease minor subtypes, respectively; and only two (33.33%) presented virus with K103N mutation. The low prevalence of drug-resistant associated mutations in Burkina Faso is encouraging. However, further studies with a larger cohort with a high non-B subtype prevalence are necessary to optimize ART in developing countries.