The Use of a Triple Nucleoside-Nucleotide Regimen for
The Use of a Triple Nucleoside-Nucleotide Regimen for
Objectives: Nonoccupational post-exposure prophylaxis (NPEP) for HIV is recommended after high-risk sexual exposure. Because of the high incidence of intolerable side effects observed with protease inhibitor- and zidovudine-based NPEP regimens, our unit changed standard NPEP treatment to 28 days of tenofovir-lamivudine-stavudine (TDF-3TC-d4T). The aim of this study was to compare side effects and numbers of individuals completing NPEP before and after this change.
Methods: Parameters were compared amongst individuals commencing the following NPEP regimens: zidovudine-lamivudine (ZDV-3TC), zidovudine-lamivudine-nelfinavir (ZDV-3TC-NFV) and TDF-3TC-d4T.
Results: A total of 385 individuals received ZDV-3TC ( n = 36), ZDV-3TC-NFV ( n = 225) or TDF-3TC-d4T ( n = 137) as NPEP for the first time between June 1999 and November 2003. Noncompletion rates were 25%, 32% and 15%, respectively ( P = 0.001), with odds ratios for noncompletion being 2.0 [95% confidence interval (CI) 0.84.8] and 2.7 (95% CI 1.64.8) in the first two groups compared with the TDF-3TC-d4T group ( P = 0.008). Adverse events were less common in the TDF-3TC-d4T group, with significantly lower rates of nausea and headache, but significantly higher rates of peripheral neuropathy and asymptomatic raised transaminases. There was no HIV seroconversion in any group.
Conclusions: TDF-3TC-d4T is significantly better tolerated than ZDV-3TC or ZDV-3TC-NFV as NPEP and results in greater numbers of individuals completing 28 days of treatment.
The use of antiretroviral therapy as nonoccupational post-exposure prophylaxis (NPEP) against HIV infection has evolved with the development of antiretroviral therapy. The rational for using antiretroviral therapy in this setting comes from pathogenesis studies, which indicate that there may be a window of opportunity to abort HIV infection by inhibiting viral replication following significant exposures to the virus. Once HIV crosses a mucosal barrier it may take up to 72 h before it is detected within the local lymph nodes and up to 5 days before it is detected in blood. Animal studies have supported these biological models, with agents such as tenofovir showing reduced infection rates.
In humans, no randomized prospective trials have been carried out to assess the efficacy of NPEP. A retrospective casecontrol series of health-care workers exposed to HIV given a 4-week course of zidovudine (ZDV) has shown an 80% reduction in the transmission rate. However, this study involved a small number of health-care workers from various countries and details were collected retrospectively. More robust human data have been obtained in the setting of vertical transmission, where antiretroviral therapy has been shown to reduce the risk of mother-to-child transmission.
Data for reduced transmission after nonoccupational and sexual exposure are lacking. In one cohort series, antiretroviral therapy was given to a group of HIV-seronegative men who had sex with men (MSM) consisting of a 28-day course of zidovudine-lamivudine. Access to NPEP did not significantly affect HIV transmission; however, only one seroconversion was observed in this group and 11 were observed in the historical controls (0.8% vs. 4.2%). Within this cohort, side effects from medications were common, with 82% of individuals reporting at least one side effect. Other series have also reported a high rate of side effects (85%, n = 79) with the use of zidovudine-containing NPEP regimens. Higher rates of NPEP completion in nonzidovudine-containing regimens have also been reported (76% vs. 94%, n = 309).
With the advent of the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), physicians administered these agents within NPEP regimens, with the aim of increasing the efficacy of therapy, as observed with the treatment of chronic HIV infection. NPEP guidelines generally recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) with or without a PI, based on physician choice according to risk assessment. Eighty-five per cent of physicians report prescribing a combination consisting of two NRTIs with a PI.
However, with the introduction of these agents, side effects have commonly been reported. Reports of hepatotoxicity (in 1062% of individuals) and fulminant hepatic failure with daily use of the NNRTI nevirapine in NPEP regimens have now limited the use of nevirapine in NPEP regimens. PIs can induce nausea, diarrhoea, hyperlipidaemia and hyperbilirubinaemia, with significant side effects in 63% of individuals. In addition, PIs do not prevent HIV integration into the host genome and so are less attractive for use in NPEP.
Because of the high incidence of intolerable side effects observed with PI-based and ZDV-based NPEP regimens, and the greater biological plausibility of triple-reverse transcriptase inhibitor-containing NPEP, our unit changed standard NPEP treatment to 28 days of tenofovir-lamivudine-stavudine (TDF-3TC-d4T). The aim of this study was to assess the number of individuals completing prescribed NPEP before and after this change and to compare side effects between different regimens.
Objectives: Nonoccupational post-exposure prophylaxis (NPEP) for HIV is recommended after high-risk sexual exposure. Because of the high incidence of intolerable side effects observed with protease inhibitor- and zidovudine-based NPEP regimens, our unit changed standard NPEP treatment to 28 days of tenofovir-lamivudine-stavudine (TDF-3TC-d4T). The aim of this study was to compare side effects and numbers of individuals completing NPEP before and after this change.
Methods: Parameters were compared amongst individuals commencing the following NPEP regimens: zidovudine-lamivudine (ZDV-3TC), zidovudine-lamivudine-nelfinavir (ZDV-3TC-NFV) and TDF-3TC-d4T.
Results: A total of 385 individuals received ZDV-3TC ( n = 36), ZDV-3TC-NFV ( n = 225) or TDF-3TC-d4T ( n = 137) as NPEP for the first time between June 1999 and November 2003. Noncompletion rates were 25%, 32% and 15%, respectively ( P = 0.001), with odds ratios for noncompletion being 2.0 [95% confidence interval (CI) 0.84.8] and 2.7 (95% CI 1.64.8) in the first two groups compared with the TDF-3TC-d4T group ( P = 0.008). Adverse events were less common in the TDF-3TC-d4T group, with significantly lower rates of nausea and headache, but significantly higher rates of peripheral neuropathy and asymptomatic raised transaminases. There was no HIV seroconversion in any group.
Conclusions: TDF-3TC-d4T is significantly better tolerated than ZDV-3TC or ZDV-3TC-NFV as NPEP and results in greater numbers of individuals completing 28 days of treatment.
The use of antiretroviral therapy as nonoccupational post-exposure prophylaxis (NPEP) against HIV infection has evolved with the development of antiretroviral therapy. The rational for using antiretroviral therapy in this setting comes from pathogenesis studies, which indicate that there may be a window of opportunity to abort HIV infection by inhibiting viral replication following significant exposures to the virus. Once HIV crosses a mucosal barrier it may take up to 72 h before it is detected within the local lymph nodes and up to 5 days before it is detected in blood. Animal studies have supported these biological models, with agents such as tenofovir showing reduced infection rates.
In humans, no randomized prospective trials have been carried out to assess the efficacy of NPEP. A retrospective casecontrol series of health-care workers exposed to HIV given a 4-week course of zidovudine (ZDV) has shown an 80% reduction in the transmission rate. However, this study involved a small number of health-care workers from various countries and details were collected retrospectively. More robust human data have been obtained in the setting of vertical transmission, where antiretroviral therapy has been shown to reduce the risk of mother-to-child transmission.
Data for reduced transmission after nonoccupational and sexual exposure are lacking. In one cohort series, antiretroviral therapy was given to a group of HIV-seronegative men who had sex with men (MSM) consisting of a 28-day course of zidovudine-lamivudine. Access to NPEP did not significantly affect HIV transmission; however, only one seroconversion was observed in this group and 11 were observed in the historical controls (0.8% vs. 4.2%). Within this cohort, side effects from medications were common, with 82% of individuals reporting at least one side effect. Other series have also reported a high rate of side effects (85%, n = 79) with the use of zidovudine-containing NPEP regimens. Higher rates of NPEP completion in nonzidovudine-containing regimens have also been reported (76% vs. 94%, n = 309).
With the advent of the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), physicians administered these agents within NPEP regimens, with the aim of increasing the efficacy of therapy, as observed with the treatment of chronic HIV infection. NPEP guidelines generally recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) with or without a PI, based on physician choice according to risk assessment. Eighty-five per cent of physicians report prescribing a combination consisting of two NRTIs with a PI.
However, with the introduction of these agents, side effects have commonly been reported. Reports of hepatotoxicity (in 1062% of individuals) and fulminant hepatic failure with daily use of the NNRTI nevirapine in NPEP regimens have now limited the use of nevirapine in NPEP regimens. PIs can induce nausea, diarrhoea, hyperlipidaemia and hyperbilirubinaemia, with significant side effects in 63% of individuals. In addition, PIs do not prevent HIV integration into the host genome and so are less attractive for use in NPEP.
Because of the high incidence of intolerable side effects observed with PI-based and ZDV-based NPEP regimens, and the greater biological plausibility of triple-reverse transcriptase inhibitor-containing NPEP, our unit changed standard NPEP treatment to 28 days of tenofovir-lamivudine-stavudine (TDF-3TC-d4T). The aim of this study was to assess the number of individuals completing prescribed NPEP before and after this change and to compare side effects between different regimens.