COMMENTARY

Human Immunodeficiency Virus Type 2

Guideline and Commentary

John G. Bartlett, MD

Disclosures

June 06, 2012

In This Article

HIV-2 Treatment

Recommendations:

  • Clinicians should include two nucleoside reverse-transcriptase inhibitors (NRTIs) and an appropriate boosted protease inhibitor (PI), such as lopinavir, saquinavir, or darunavir, when prescribing ART for HIV-2 mono-infected or HIV-1/HIV-2 co-infected individuals (see Table 2). (AIII)

  • Clinicians should not prescribe non-nucleoside reverse-transcriptase inhibitors (NNRTIs) or the PIs nelfinavir, atazanavir, or fosamprenavir as part of an ART regimen against HIV-2 mono-infection; these agents may be used as part of a regimen for HIV-1/HIV-2 co-infected patients if adequate treatment for HIV-2 is also included.[20] (BIII)

  • Clinicians should consult with a provider with experience in the management of HIV-2 before initiating ART in HIV-2-infected patients. (AIII)

  • Clinicians should educate patients with confirmed HIV-2 infection about the lack of data regarding treatment of HIV-2 and should review individual benefits and risks of initiating treatment. Patients should make the final decision of whether and when to initiate ART.

No randomized clinical trials have been conducted to determine when to initiate ART in the setting of HIV-2 infection, and the best choices of therapy for HIV-2 infection remain under study. Because the optimal treatment strategy for HIV-2 infection has not been defined, the recommendations provided in this section are based on this committee's expert opinion.

Although HIV-2 is generally less aggressive, and progression to AIDS is less frequent, HIV-2 responds less predictably to ART when progression occurs, and response is more difficult to monitor (see Table 2 for available data regarding HIV-2 response to ART). The standard methods and interpretation protocols that are used to monitor ART for HIV-1-infected patients may not apply for HIV-2-infected patients. Some ART regimens that are appropriate for HIV-1 infection may not be as effective for HIV-2. The following factors should be considered when deciding whether or not to initiate ART in HIV-2-infected patients:

  • The majority of HIV-2-infected patients are long-term nonprogressors

  • HIV-2 may confer more rapid resistance to ART agents due to wild-type genetic sequence that results in a significant increase in resistance to ART agents compared with HIV-1[21,22,23]

  • Pathways for the development of drug mutations may differ between the two viruses

  • Recent data have shown a significant reduction in HIV-1 transmission risk between serodiscordant heterosexual couples when the positive partner was receiving ART[24]; lower viral load level may also reduce HIV-2 transmission risk

Key Point
Few data exist for the diagnosis and management of HIV-1/HIV-2 co-infection; however, clinical management currently focuses on controlling HIV-1 infection with agents that are active against both HIV-1 and HIV-2.

 

Table 2. Efficacy of Antiretroviral Therapy Against HIV-2 Infection

NRTIs
  • Although most in vitro studies have shown that similar concentrations of NRTIs are needed to block both HIV-1 and HIV-2 replication, data suggest that some NRTIs may not be as effective against HIV-2.[25] For example, HIV-1 more readily incorporates zidovudine and is more susceptible to zidovudine than HIV-2, and there is a lower barrier to resistance with HIV-2 than with HIV-1.[21,26]

  • Genotypic analysis of HIV-2-infected patients on ART has shown that many of the same amino acid substitutions that are associated with NRTI resistance in HIV-1 may be implicated in HIV-2. Some resistance mutations (K65R, Q151M, and M184V) in combination can confer class-wide NRTI resistance and cause rapid virologic failure.[21]

NNRTIs
  • NNRTIs block HIV-1 reverse transcription through a specific binding site that is not present in HIV-2; this class of drugs will not be effective against HIV-2.[27,28]

  • HIV-2 appears to be intrinsically resistant to NNRTIs[27]; the Y188L polymorphism appears naturally in all HIV-2 isolates. Reversion to Y188 restores the reverse transcriptase sensitivity to some NNRTIs, including efavirenz and delavirdine.[29]

  • In general, NNRTIs inhibit HIV-2 at effective concentrations that are at least 50-fold higher than those that inhibit HIV-1,[30] making the use of these drugs for HIV-2 infection problematic.

  • Etravirine appears to have limited activity against HIV-2, but this may not be clinically relevant because the mean 50% effective concentration in MT4 cells is 2500-fold higher than that observed for HIV-1.[31]

PIs
  • PIs appear to have variable activity and accelerated genotypic resistance.[23]

  • HIV-2 expresses natural polymorphisms in the protease that may be implicated in emergent drug resistance and accelerate time to development of PI resistance.[23]

  • One study noted that the pathways for HIV-2 protease drug resistance may differ from those for HIV-1.[25]

  • Saquinavir, lopinavir, and darunavir have shown comparable activity against HIV-1 and HIV-2.[32,33,34]

  • Indinavir, nelfinavir, and ritonavir may be less active against HIV-2 than HIV-1.

  • Atazanavir has lower and variable activity against HIV-2 in comparison with HIV-1.[33]

  • The data regarding tipranavir are conflicting.

  • Some natural polymorphisms in HIV-2 may confer baseline resistance to fosamprenavir.

Integrase inhibitors
  • Little is known about the use of integrase inhibitors in HIV-2 infection.

  • The integrase inhibitors raltegravir and elvitegravir have demonstrated activity in vitro.[35] Clinical response to raltegravir was reported in a patient with highly treatment-experienced HIV-2 infection,[36] but the emergence of mutations was reported in another patient.[37]

CCR5 co-receptor antagonists
  • The activity of maraviroc has been limited to patients with CCR5-tropic viruses.

  • Primary HIV-2 isolates can utilize a broad range of co-receptors, including CXCR4, CCR5, CCT-5, GPR15, and CXCR6. This limits the therapeutic utility of maraviroc in HIV-2 infection.

Fusion inhibitors
  • HIV-2 is intrinsically resistant to the fusion inhibitor enfuvirtide.[30,38]

 

As with disease monitoring, monitoring of response to treatment for HIV-2 is more challenging than for HIV-1. Viral load and ART resistance assays for HIV-2 are not commercially available. However, such tests may be available under research Investigational New Drug (IND) protocols. Results generated by these assays should be interpreted with caution due to the IND classification and the absence of standardized interpretation protocols.[11] An HIV-2 viral load assay developed by NYSDOH Wadsworth Center is currently undergoing validation for clinical use. Contact the laboratory regarding availability at 518-474-2163.

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