Bartlett HIV/AIDS Review: February 1, 2006
Bartlett HIV/AIDS Review: February 1, 2006
Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192:1537-1544.
Summary: Previous studies have shown that patients with virologic failure and multiple resistance mutations appear to benefit from continuing antiretroviral therapy. The evidence is based on the substantial increase in viral load and rapid decline in CD4+ cells at the time that seemingly unsuccessful antiretroviral therapy is discontinued. The current study group, led by Steve Deeks, hypothesized that treatment directed at preventing emergence of wild-type virus, with maintenance of a less fit or less virulent drug-resistant variant, might account for this observation. They further suggest that a simplified regimen could achieve this goal and offer the benefit of reduced drug cost and toxicity. To test this hypothesis, they conducted a 48-week study in adults with multidrug-resistant HIV, and then discontinued selected classes of agents to determine impact on viral load, CD4+ cell count, and resistance mutations. At baseline, the patients had a median reduction in HIV viral load of 1.2 log10 copies/mL compared with the pretreatment baseline. Drug interruptions included the protease inhibitor (PI) in 18 subjects, nonnucleoside reverse transcriptase inhibitor (NNRTI) in 6, and nucleoside reverse transcriptase inhibitor (NRTI) in 6. These results are summarized below and in Table 1 .
Conclusion: The authors concluded that their data show that NRTIs appear to be responsible for continued antiviral activity in the setting of multiple drug-resistant mutations. Most NRTIs and PIs can select for drug-resistance mutations that can reduce viral fitness.
Commentary: This has been a major effort of Steve Deeks, who made the original observation regarding the benefit of "failed antiretroviral therapy" in terms of viral load and CD4+ cell count. The results support his original bias in terms of showing the important role of the nucleosides, although data are supplied only for lamivudine. The results seem to support other studies that indicate that the lamivudine-associated 184V mutation accounts for a reduction of about 0.5 log10 copies/mL, roughly half of the average decrease of 1.2 log10 copies/mL. The results of this trial also seem to support a potential role of other NRTIs, a minor role for PIs and, as expected, no role for resistant NNRTIs. The rapid increase in viral load after stopping lamivudine indicates that this effect cannot be due to the 184V mutation causing reduced replication capacity, because the reversion of 184V took place much later.
Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr. 2005;40:280-287.
Summary: This is a report from Madrid of a study designed to evaluate maintenance treatment with lopinavir/ritonavir monotherapy vs continuing lopinavir/ritonavir plus 2 nucleosides in patients who have achieved good viral suppression for a sustained period. It is a randomized, controlled, open-label proof-of-concept pilot trial. Eligibility criteria were antiviral treatment with viral suppression (< 50 copies/mL) for 6 months and lopinavir/ritonavir for at least 4 weeks. There were 42 participants, including 21 in each arm. Results showed virologic failure in 3 patients in the monotherapy arm and in 1 patient in the group that continued lopinavir/ritonavir-based highly active antiretroviral therapy (HAART) at 48 weeks. The 3 failures in the monotherapy category responded with the addition of 2 nucleosides and had no major PI resistance mutations. Data are summarized in Table 2 .
Conclusion: The authors concluded that per their study, this therapeutic tactic shows promise and should be subject to a larger trial.
Commentary: There are 3 previous trials of "induction-maintenance treatment," and all 3 required premature discontinuation due to virologic failure. The unusual feature of the current study was the demonstration of response with readministration of 2 nucleosides and the lack of resistance mutations.
Sterne JA, Hernan MA, Ledergerber B, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2005;366:378-384.
Summary: Sterne and colleagues evaluated the effectiveness of HAART using observational analysis of the Swiss HIV cohort. The patients were enrolled after January 1996 when HAART became available in Switzerland. The analysis included 2161 patients with a median follow-up of 54 months and a total observation time of 13,962 patient-years; HAART was given for 7145 (51%) patient-years. The overall results for HAART vs no HAART showed a survival odds ratio of 0.14. HAART became more beneficial with increasing time of use and was less effective in those with injection-drug use as a risk factor. There was no clear benefit with the analysis based on baseline CD4+ cell count, sex, or age above or below 40 years, as shown in Table 3 .
Conclusion: The results demonstrate the substantial benefit of HAART.
Commentary: Several other studies have shown similar results. The difference with this current study is that it shows a longer follow-up, and this may account for the extraordinarily impressive odds ratio of 0.13.
Novak RM, Chen L, MacArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients; implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis. 2005;40:468-474.
Summary: This is a report from the Community Programs for Clinical Research on AIDS (CPCRA) study that was designed to define the prevalence of drug resistance among treatment-naive patients in 25 US cities during 1999-2001. Genotypic testing was done on strains from 491 chronically HIV-infected patients using the criteria of IAS-USA 2003 to define resistance. The results showed resistance mutations in 57 of the 491 strains (11.6%). The breakdown by drug category and major resistance mutations is summarized in Table 4 .
Chun TW, Nickle DC, Justement JS, et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest. 2005;115:3250-3255.
Summary: Chun and colleagues note that persistence of latently infected CD4+ cells is the major limitation in preventing HIV eradication, even in patients who have successful viral suppression for sustained periods. The present study involved 11 subjects who had sustained viral suppression to < 50 copies/mL for an average of 8.3 years. As previously demonstrated by Bob Siliciano's group, these patients had persistence of replication-competent virus in resting CD4+ cells. Further studies of the resting pool of CD4+ cells showed that they did not produce detectable levels of HIV. However, activated CD4+ cells did release HIV, indicating the capacity for production of new virions that persisted in this cellular compartment. Substantially higher levels of HIV proviral DNA were found in the activated CD4+ cells, and phylogenetic analysis showed evidence of cross-infection between the resting and activated CD4+ cell compartments, which indicated continuing reactivation of the latent pool.
Conclusion: Chun and colleagues concluded that the therapeutic implications of their observations are:
Tipranavir (Aptivus) for HIV. Medical Letter. 2005;47:83.
Clinical Trials: The 24-week results with ritonavir-boosted tipranavir in patients with PI-resistant strains showed a viral load < 50 copies/mL in 24% of the tipranavir-treated patients compared with 9% in the comparator group. Patients who received tipranavir plus enfuvirtide had a better response than those who received tipranavir without (58% vs 35%).
Adverse Effects: Severe hepatitis including some fatalities has been reported in patients receiving tipranavir; careful monitoring of liver function, especially for coinfection with HCV or HBV, is warranted.
Drug Interactions: There are extensive drug reactions, including a 50% reduction in serum concentrations of methadone. Tipranavir causes substantial reductions in serum concentrations of amprenavir, lopinavir, and saquinavir; tipranavir should not be used with these PIs.
Cost:Table 5 provides a comparison of costs of currently available PIs.
Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192:1537-1544.
Summary: Previous studies have shown that patients with virologic failure and multiple resistance mutations appear to benefit from continuing antiretroviral therapy. The evidence is based on the substantial increase in viral load and rapid decline in CD4+ cells at the time that seemingly unsuccessful antiretroviral therapy is discontinued. The current study group, led by Steve Deeks, hypothesized that treatment directed at preventing emergence of wild-type virus, with maintenance of a less fit or less virulent drug-resistant variant, might account for this observation. They further suggest that a simplified regimen could achieve this goal and offer the benefit of reduced drug cost and toxicity. To test this hypothesis, they conducted a 48-week study in adults with multidrug-resistant HIV, and then discontinued selected classes of agents to determine impact on viral load, CD4+ cell count, and resistance mutations. At baseline, the patients had a median reduction in HIV viral load of 1.2 log10 copies/mL compared with the pretreatment baseline. Drug interruptions included the protease inhibitor (PI) in 18 subjects, nonnucleoside reverse transcriptase inhibitor (NNRTI) in 6, and nucleoside reverse transcriptase inhibitor (NRTI) in 6. These results are summarized below and in Table 1 .
PI treatment interruption, n = 18
Stable viral load through week 24: Mean HIV change: 0.005 log10 copies/mL (P = 0.3)
CD4+ cell count, median time to 25% decrease = 24 weeks
PI resistance mutation reverted in 6/18 at 12-36 weeks; no reversions through week 42 in 12/18
NRTI treatment interruption, n = 6
Viral load (VL) increased > 0.5 log10 in 2-3 weeks
Reversion of M184V in 5 of 6 at median 20 weeks
VL increased median of 0.4 log10 when resistance was reversed
NNRTI treatment interruption, n = 6
VL: no significant change at week 2 or 4
Conclusion: The authors concluded that their data show that NRTIs appear to be responsible for continued antiviral activity in the setting of multiple drug-resistant mutations. Most NRTIs and PIs can select for drug-resistance mutations that can reduce viral fitness.
Commentary: This has been a major effort of Steve Deeks, who made the original observation regarding the benefit of "failed antiretroviral therapy" in terms of viral load and CD4+ cell count. The results support his original bias in terms of showing the important role of the nucleosides, although data are supplied only for lamivudine. The results seem to support other studies that indicate that the lamivudine-associated 184V mutation accounts for a reduction of about 0.5 log10 copies/mL, roughly half of the average decrease of 1.2 log10 copies/mL. The results of this trial also seem to support a potential role of other NRTIs, a minor role for PIs and, as expected, no role for resistant NNRTIs. The rapid increase in viral load after stopping lamivudine indicates that this effect cannot be due to the 184V mutation causing reduced replication capacity, because the reversion of 184V took place much later.
Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr. 2005;40:280-287.
Summary: This is a report from Madrid of a study designed to evaluate maintenance treatment with lopinavir/ritonavir monotherapy vs continuing lopinavir/ritonavir plus 2 nucleosides in patients who have achieved good viral suppression for a sustained period. It is a randomized, controlled, open-label proof-of-concept pilot trial. Eligibility criteria were antiviral treatment with viral suppression (< 50 copies/mL) for 6 months and lopinavir/ritonavir for at least 4 weeks. There were 42 participants, including 21 in each arm. Results showed virologic failure in 3 patients in the monotherapy arm and in 1 patient in the group that continued lopinavir/ritonavir-based highly active antiretroviral therapy (HAART) at 48 weeks. The 3 failures in the monotherapy category responded with the addition of 2 nucleosides and had no major PI resistance mutations. Data are summarized in Table 2 .
Conclusion: The authors concluded that per their study, this therapeutic tactic shows promise and should be subject to a larger trial.
Commentary: There are 3 previous trials of "induction-maintenance treatment," and all 3 required premature discontinuation due to virologic failure. The unusual feature of the current study was the demonstration of response with readministration of 2 nucleosides and the lack of resistance mutations.
Sterne JA, Hernan MA, Ledergerber B, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet. 2005;366:378-384.
Summary: Sterne and colleagues evaluated the effectiveness of HAART using observational analysis of the Swiss HIV cohort. The patients were enrolled after January 1996 when HAART became available in Switzerland. The analysis included 2161 patients with a median follow-up of 54 months and a total observation time of 13,962 patient-years; HAART was given for 7145 (51%) patient-years. The overall results for HAART vs no HAART showed a survival odds ratio of 0.14. HAART became more beneficial with increasing time of use and was less effective in those with injection-drug use as a risk factor. There was no clear benefit with the analysis based on baseline CD4+ cell count, sex, or age above or below 40 years, as shown in Table 3 .
Conclusion: The results demonstrate the substantial benefit of HAART.
Commentary: Several other studies have shown similar results. The difference with this current study is that it shows a longer follow-up, and this may account for the extraordinarily impressive odds ratio of 0.13.
Novak RM, Chen L, MacArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients; implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis. 2005;40:468-474.
Summary: This is a report from the Community Programs for Clinical Research on AIDS (CPCRA) study that was designed to define the prevalence of drug resistance among treatment-naive patients in 25 US cities during 1999-2001. Genotypic testing was done on strains from 491 chronically HIV-infected patients using the criteria of IAS-USA 2003 to define resistance. The results showed resistance mutations in 57 of the 491 strains (11.6%). The breakdown by drug category and major resistance mutations is summarized in Table 4 .
Chun TW, Nickle DC, Justement JS, et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest. 2005;115:3250-3255.
Summary: Chun and colleagues note that persistence of latently infected CD4+ cells is the major limitation in preventing HIV eradication, even in patients who have successful viral suppression for sustained periods. The present study involved 11 subjects who had sustained viral suppression to < 50 copies/mL for an average of 8.3 years. As previously demonstrated by Bob Siliciano's group, these patients had persistence of replication-competent virus in resting CD4+ cells. Further studies of the resting pool of CD4+ cells showed that they did not produce detectable levels of HIV. However, activated CD4+ cells did release HIV, indicating the capacity for production of new virions that persisted in this cellular compartment. Substantially higher levels of HIV proviral DNA were found in the activated CD4+ cells, and phylogenetic analysis showed evidence of cross-infection between the resting and activated CD4+ cell compartments, which indicated continuing reactivation of the latent pool.
Conclusion: Chun and colleagues concluded that the therapeutic implications of their observations are:
There should be consideration of methods to reduce cellular activation because this appears to contribute to persistence of HIV.
The persistence of HIV in activated CD4+ cells despite undetectable viremia suggests that intensification -- even in aviremic patients -- may be advised. Specific suggestions are the addition of a new class of drugs, such as HIV entry inhibitors.
Tipranavir (Aptivus) for HIV. Medical Letter. 2005;47:83.
Clinical Trials: The 24-week results with ritonavir-boosted tipranavir in patients with PI-resistant strains showed a viral load < 50 copies/mL in 24% of the tipranavir-treated patients compared with 9% in the comparator group. Patients who received tipranavir plus enfuvirtide had a better response than those who received tipranavir without (58% vs 35%).
Adverse Effects: Severe hepatitis including some fatalities has been reported in patients receiving tipranavir; careful monitoring of liver function, especially for coinfection with HCV or HBV, is warranted.
Drug Interactions: There are extensive drug reactions, including a 50% reduction in serum concentrations of methadone. Tipranavir causes substantial reductions in serum concentrations of amprenavir, lopinavir, and saquinavir; tipranavir should not be used with these PIs.
Cost:Table 5 provides a comparison of costs of currently available PIs.