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The Use of a Triple Nucleoside-Nucleotide Regimen for Nonoccupational HIV Post-Exposure Prophylaxis
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HIV Medicine
May 2005
"....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..."
A Winston1,2, J McAllister1, J Amin2, DA Cooper1,2 and A Carr11Department of Immunology, HIV and Infectious Diseases, St Vincent's Hospital, Sydney, Australia, and 2National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
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) 0.8-4.8] and 2.7 (95% CI 1.6-4.8) 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.
INTRODUCTION
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 [1,2]. Animal studies have supported these biological models [3,4], with agents such as tenofovir showing reduced infection rates [5].
In humans, no randomized prospective trials have been carried out to assess the efficacy of NPEP. A retrospective case-control 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 [6]. 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 [7].
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 [8]. 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 [9]. Higher rates of NPEP completion in nonzidovudine-containing regimens have also been reported (76% vs. 94%, n=309) [10].
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 [11-14]. Eighty-five per cent of physicians report prescribing a combination consisting of two NRTIs with a PI [15].
However, with the introduction of these agents, side effects have commonly been reported. Reports of hepatotoxicity (in 10-62% 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 [16-18]. PIs can induce nausea, diarrhoea, hyperlipidaemia and hyperbilirubinaemia, with significant side effects in 63% of individuals [19-21]. 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.
AUTHOR DISCUSSION
The use of TDF-3TC-d4T is significantly better tolerated as a NPEP regimen than ZDV-3TC or ZDV-3TC-NFV and results in a significantly greater number of individuals completing 28 days of treatment. Compared with the other two treatment strategies, TDF-3TC-d4T was associated with lower rates of patients being lost to follow-up, NPEP being discontinued because of side effects, and NPEP treatment being changed, and so may lead to a lower incidence of treatment failure. Side effects were generally less common, with significantly lower rates of diarrhoea, headache and nausea. However, significantly higher rates of peripheral neuropathy, raised liver enzymes, dizziness and flatulence were observed in the TDF-3TC-d4T group. These observed side effects were associated with significantly fewer individuals stopping or changing therapy than the side effects observed with the other treatment regimens.
Previously reported rates of completion for NPEP in individuals prescribed ZDV-3TC from two published series vary from 75% to 89% [8,10]. Our current clinic protocol is associated with a similar completion rate in this group of 81%.
From our cohort, we can estimate the number of expected HIV seroconversions without the use of NPEP by assessing an individual's risk associated with exposure type [22-25] and the local baseline HIV seroprevalence [26]. From this, we would have expected 1.21 (0.37%; 95% CI 1.14-1.28) infections in our cohort without the use of NPEP. We cannot measure the efficacy in preventing seroconversion, however, because of the sample size and lack of randomization.
Our study has additional limitations. No measure of adherence to medication was used. Almost all of our cohort are men. Reasons for patients being lost to follow-up are not recorded and may be independent of NPEP regimen prescribed. Peripheral neuropathy and asymptomatic raised liver enzymes were observed but were reversible with a short course of d4T. A better option for this treatment strategy might therefore be a third agent that does not cause peripheral neuropathy or the use of only TDF-3TC.
Within our cohort, the seroprevalence of HBV is low [26]. In other areas with a higher prevalence of HBV, the short-term use of TDF-3TC may be associated with hepatitis flares on withdrawal of treatment. However, this could also be associated with the use of 3TC alone, as is current common practice. Furthermore, all individuals in our cohort had normal liver function test results at baseline. With a 19% observed incidence in rise of serum transaminase with a 28-day course of TDF-3TC-d4T, its use in individuals with abnormal liver function tests or known hepatic disease needs further evaluation.
Rates of baseline HIV nucleoside-associated resistance are increasing. Low rates of transmitted baseline resistance have been reported within our area [27]; however, in areas where rates are higher, a triple nucleoside-nucleotide regimen may not be appropriate. Triple-nucleoside regimens for the treatment of HIV infection have been associated with poor virological results [28]. Although the incremental benefit of drug combinations active at different stages of viral replication is speculative in NPEP, more robust data are needed.
Future options for NPEP regimens include a once-daily regimen of TDF-3TC-d4T using the d4T-extended release (XR) once-daily formulation in development [29]. Regimens containing NNRTIs other than nevirapine may have increased efficacy as NPEP in view of efavirenz-containing regimens showing superiority over triple-nucleoside regimens in the treatment of chronic HIV infection [28]. With the development of new NNRTIs such as TMC-125 [30] and new fixed-dose combination preparations such as emtricitabine-tenofovir-efavirenz, further work to assess the safety and tolerability of these regimens is needed.
METHODS
The department of Immunology, HIV and Infectious Diseases, St. Vincent's Hospital, Sydney, Australia instituted a standard procedure for the administration of NPEP to individuals presenting after high-risk exposures in June 1999. This involved an initial assessment at presentation to the emergency department or out-patient clinic for exposure risk and medical history with analysis of the following laboratory parameters: HIV antibody, hepatitis B and hepatitis C serology, urea and electrolytes, liver function tests, full blood count and, in female patients, serum beta-human chorionic gonadotrophin (betaHCG).
Individuals with a significant exposure risk [e.g. unprotected receptive anal sex (RAS)] commenced a 28-day course of NPEP, and were reviewed for assessment of side effects and their management at weeks 1, 2 and 6; for safety laboratory parameters at week 2 (urea and electrolytes, liver function tests, venous lactate and full blood count); for HIV antibody testing at weeks 12 and 24; and for repeat hepatitis B and C serology at week 24.
From June 1999 until November 2002, individuals were prescribed a 28-day course of ZDV 300 mg and lamivudine 150 mg orally in a fixed-dose combination tablet twice daily (ZDV-3TC) or a 28-day course of ZDV-3TC with nelfinavir 1250 mg orally twice daily (ZDV-3TC-NFV) depending on physician choice and perceived magnitude of HIV exposure risk.
In December 2002, standard NPEP was changed to a 28-day course of tenofovir 300 mg daily, lamivudine 300 mg daily and stavudine 40 mg twice daily orally (TDF-3TC-d4T). The stavudine dose was weight-adjusted for individuals weighing less than 60 kg.
Parameters were compared between individuals commencing ZDV-3TC and ZDV-3TC-NFV between June 1999 and November 2002 and TDF-3TC-d4T between December 2002 and November 2003. The primary outcome of interest was the proportion of individuals completing prescribed NPEP. The clinic protocol for prescribing NPEP, and for data recorded at each visit and follow-up, did not change between June 1999 and November 2003. Data were collected from case note review. Episodes where individuals received a NPEP regimen on more than one occasion were excluded from the analysis and episodes where individuals received a different NPEP regimen were included in the analysis. Changes to antiretroviral therapy were defined as changes to any drug in the regimen. Individuals who did not complete the designated baseline 28-day NPEP regimen were defined as 'not-completed-assigned-regimen' and those not completing a 28-day course of treatment were defined as 'not-completed-NPEP'.
Data were analysed using stata statistical software (V8.0; STATA-CORP LP, College Station, TX, USA). Chi-squared statistics were used to test for associations between categorical variables. Logistic regression was used to adjust the association of percentage completing therapy for any measures that were imbalanced of baseline. All P-values presented are two-tailed, with values less than 0.05 being considered significant.
RESULTS
Patients
A total of 456 prescriptions of NPEP were issued (Fig. 1). Of these, 28 (6.1%) episodes involved individuals being prescribed regimens outside the current protocol, as a consequence of source patients having documented HIV viral isolates with resistance-associated mutations. Of the remaining episodes, 30 were excluded from the analysis as they were associated with individuals having a given NPEP regimen on more than one occasion. A total of 398 episodes were analysed, representing 385 individuals.
These 398 prescriptions represented 36 (9%) ZDV-3TC, 225 (57%) ZDV-3TC-NFV and 137 (34%) TDF-3TC-d4T (Table 1). Median time to commencing NPEP from time of exposure was 18 h, with 90% of individuals commencing therapy within 48 h.
There was no significant difference in age or sex amongst groups. The commonest exposure risk was RAS in all groups (42%, 51% and 61%, respectively). Needle stick exposure (NSE) was a commoner exposure risk in the ZDV-3TC group as compared with the other groups.
Outcomes
At baseline, no individual had evidence of active hepatitis B virus (HBV) infection (HBV surface antigen positive) or of hepatitis C virus (HCV) infection (HCV antibody positive). No HIV, HBV or HCV seroconversion was observed in any group after 6 months of follow-up.
Noncompletion rates for the prescribed regimens were 25%, 32% and 15%, respectively, for the three regimens (P=0.001), with odds ratios for noncompletion of 2.0 [95% confidence interval (CI) 0.8-4.8] and 2.7 (95% CI 1.6-4.8) in the ZDV-containing groups relative to the TDF-3TC-d4T group (Fig. 2).
After adjustment for exposure risk, completion rates remained associated with prescribed regimens (P=0.004).
Allowing for completion after one or more changes to NPEP regimens, there was still a higher success rate in the TDF-3TC-d4T group, with noncompletion rates of 19%, 27% and 14% in the three groups, respectively (P=0.012; P=0.015 adjusted for exposure risk).
Amongst the three regimens, there were no differences in patients stopping therapy as a consequence of the patient testing HIV-positive at baseline (n=3, stopped NPEP on days 4, 11 and 11), the source testing HIV-negative at baseline (n=22, mean time to stopping NPEP 7 days, 95% CI 4-10) or the patient deciding to stop therapy (n=2, stopped NPEP on days 1 and 6).
The patient being lost to follow-up was more common in the ZDV-3TC and ZDV-3TC-NFV groups than in the TDF-3TC-d4T group (11.1%, 13.8% and 5.8%, respectively; P=0.062), although this was not statistically significant. Stopping NPEP therapy because of side effects was also more common in the ZDV-containing groups (8.3%, 5.8% and 0.7%, respectively; P=0.032), as was changing antiretroviral therapy during the 28 days of treatment (5.6%, 8.4% and 1.5%, respectively; P=0.022). A variety of changes to drug regimens were made as described in Table 2. Of interest, 19 individuals on ZDV-3TC-NFV changed therapy, with eight individuals stopping NFV because of diarrhoea and 11 individuals stopping ZDV because of nausea.
Adverse events occurring in more than 1% of individuals and all grade 3/4 adverse events are shown in Table 3. The commonest laboratory adverse event was an elevated level of serum transaminases, which was observed more commonly in the TDF-3TC-d4T group than in the other groups. This represents 26 individuals (19%) in the TDF-3TC-d4T group. Of these, 23 had grade 1 transaminase elevation. One individual ceased NPEP at week 2 in the ZDV-3TC group, after developing anaemia (haemoglobin drop from 14.5 to 10.5 g/dL) and dizziness.
Nausea and diarrhoea were the commonest clinical adverse events. Nausea and headache were more common in the ZDV-3TC and ZDV-3TC-NFV groups than in the TDF-3TC-d4T group, with diarrhoea being more common in the ZDV-3TC-NFV group. Fatigue was commonly observed with all NPEP regimens.
Peripheral neuropathy was observed in eight individuals in the TDF-3TC-d4T group. These were all grade 1 events. Furthermore, dizziness and flatulence were significantly more common in this group in a small number of individuals (eight and five patients, respectively). All peripheral neuropathy events and other clinical adverse events resolved by 2 weeks after completion of NPEP therapy.
The only adverse event significantly associated with discontinuation of therapy was vomiting.
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